Methods of treatment using phenyl indole allosteric inhibitors of p97 atpase

ABSTRACT

The present invention is directed to methods of inhibiting p97 and compounds and compositions useful in such methods. Diseases and conditions the can be treated with the compounds and compositions of the invention include, but are not limited to, cancer and neurodegenerative disorders susceptible to treatment by inhibition of p97.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.16/748,654, filed Jan. 21, 2020, which is a Divisional of U.S. patentapplication Ser. No. 15/769,987, filed Apr. 20, 2018, now U.S. Pat. No.10,633,370, which is the U.S. National Stage of International PatentApplication No. PCT/US2016/057869, filed Oct. 20, 2016, which claimspriority to U.S. Provisional Patent Application No. 62/244,497, filedOct. 21, 2015, and all of these applications are incorporated herein byreference in their entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under HHSN261200800001Eawarded by the National Institutes of Health. The government has certainrights in the invention.

BACKGROUND

The AAA ATPase p97 (also known as valosin-containing protein (VCP),Cdc48 in yeast and plants, CDC-48 in worms and Ter94 in flies), is ahexameric member of the \AAA family (ATPases associated with diversecellular activities). Zhang et al., “Structure of the AAA ATPase p97,”Molecular Cell, 6(6): 1473-84 (2000).

Recent studies have uncovered cellular functions for p97 in autophagy,endosomal sorting and regulating protein degradation at the outermitochondrial membrane, and elucidated a role for p97 in keychromatin-associated processes. These findings extend the functionalrelevance of p97 to lysosomal degradation and reveal a dual role inprotecting cells from protein stress and ensuring genome stabilityduring proliferation. Meyer et al., “Emerging functions of the VCP/p97AAA-ATPase in the ubiquitin system,” Nature Cell Biology, 14: 117-123(2012).

p97 also functions as an interaction hub, and different sets of at least30 cofactors have been shown to be responsible for modulatingp97-mediated processes. Meyer et al., “The VCP/p97 system at a glance:connecting cellular function to disease pathogenesis,” J. of Cell Sci.,127: 1-7 (2014).

p97-associated disease and possible mechanisms: p97 is a potentialtherapeutic target for cancer and neurodegenerative diseases. Given thecrucial role of p97 in maintaining cellular proteostasis, it is notsurprising that autosomal dominant mutations in p97, the gene encodingp97, lead to a rare multisystem degenerative disorder previously termedIBMPFD/ALS. The acronym IBMPFD/ALS refers to the four main phenotypesthat can affect patients carrying disease-associated mutations of p97(i.e., inclusion body myopathy (IBM), Paget's disease of the bone (PDB),frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)).However, a patient with a pathogenic p97 mutation can have any mixtureof phenotypes, including all four phenotypes or just one phenotype inisolation. In addition, a member of the same family can have anycombination of phenotypes. Id.

Some carriers of p97 mutation also manifest additional symptoms,including Parkinsonism, ataxia, cataracts, dilated cardiomyopathy,hepatic fibrosis, and hearing loss. The term multisystem proteinopathy’has been proposed as the nomenclature for an emerging family of geneticdisorders that are unified by this characteristic variation in thepenetrance of muscle, bone and CNS degenerative phenotypes along withthe accumulation of ubiquitin and TDP-43-positive inclusions.

p97 and cancer: p97 figures prominently in protein quality control aswell as serving a variety of other cellular functions associated withcancer. As found for other chaperones, various forms of cancer,including breast, lung, pancreatic, and colorectal cancer, upregulatep97 as a response to accelerated growth and deteriorating proteinquality control. See Brandvold et al, “The chemical biology of molecularchaperones—implications for modulation of proteostasis,” J. Mol. Biol.,427(18): 2931-2947 (2015); Manos-Turvey et al., “The effect of structureand mechanism of the Hsp70 chaperone on the ability to identify chemicalmodulators and therapeutics,” Top. Med. Chem., 16:1-49 (2015); Deshaies,R. J., “Proteotoxic crisis, the ubiquitin-proteasome system, and cancertherapy,” BMC Biology, 12: 94/1-94/14 (2014); and Haines, D. S.,“P97-containing complexes in proliferation control and cancer: Emergingculprits or guilt by association?” Genes Cancer, 1:753-763 (2010). Thisproperty might render cancer cells more sensitive to p97 inhibitors thannormal cells. In particular, combinations with proteasome or heat shockprotein inhibitors could further widen the therapeutic window, but thetest of this hypothesis awaits the development of clinically efficaciousp97 antagonists.

Several small molecule inhibitors of p97 have been identified. SeeDavies et al., “Improved structures of full-length p97, an AAA ATPase:Implications for mechanisms of nucleotide-dependent conformationalchange,” Structure, 16:715-726 (2008). This includes severalamino-heterocycles, such as the diaminoquinazolines 1, 2, and 3,aminothiazole 4, and the irreversible inhibitor chloroacetamide 5 (FIG.1). See Chou et al., “Reversible inhibitor of p97, DBeQ, impairs bothubiquitin-dependent and autophagic protein clearance pathways,” Proc.Natl. Acad. Sci. USA, 108:4834-4839 (2011); Fang et al., “Evaluating p97inhibitor analogues for their domain selectivity and potency against thep97-p47 complex,” ChemMedChem, 10, 52-56 (2015); Zhou et al.,“Preparation of fused pyrimidines as inhibitors of p97 complex,” WO2014/015291; Chem. Abstr., 160:248915 (2014); Bursavich et al.,“2-Anilino-4-aryl-1,3-thiazole inhibitors of valosin-containing protein(VCP or p97),” Bioorg. Med. Chem. Lett., 20:1677-1679 (2010); Magnaghiet al., “Covalent and allosteric inhibitors of the ATPase VCP/p97 inducecancer cell death,” Nat. Chem. Biol., 9:548-556 (2013). 1,2,4-Triazole6, sulfonate 7, and imidazolinone 8 were identified by high throughputscreening campaigns, whereas the discovery of the anticancer agent 9(sorafenib) and the natural products 10 (withaferin A) and 11(rheoemodin) as p97 inhibitors was based on specific mechanism of actionand targeted lead identification studies. See Polucci et al.,“Alkylsulfanyl-1,2,4-triazoles, a new class of allosteric valosinecontaining protein inhibitors. Synthesis and structure-activityrelationships,” J. Med. Chem., 56: 437-450 (2013); Kakizuka et al.,“Preparation of 2-(arylazo orheteroarylazo)-4-aminonaphthalene-1-sulfonic acid derivatives asregulators of vasolin-containing protein (VCP),” WO 2012/014994; Wang etal., “Inhibition of p97-dependent protein degradation by eeyarestatinI,” J. Biol. Chem., 283: 7445-7454 (2008); Yi et al.,“Sorafenib-mediated targeting of the AAA+ ATPase p97/VCP leads todisruption of the secretory pathway, endoplasmic reticulum stress, andhepatocellular cancer cell death,” Mol. Cancer Ther., 11:2610-2620(2012); Tao et al., “Withaferin A analogs that target the AAA+ chaperonep97,” ACS Chem. Biol., 10(8): 1916-1924 (2015); Kang et al., “Functionalchromatography reveals three natural products that target the sameprotein with distinct mechanisms of action,” ChemBioChem, 15, 2125-2131(2014).

There remains a need in the art for inhibitors of p97, useful intreating cancer and neurodegenerative disorders caused by proteostaticmalfunction. The present invention satisfies these needs.

SUMMARY OF THE DISCLOSED SUBJECT MATTER

The present invention is directed to methods of inhibiting p97 andcompounds and compositions useful in such methods. Diseases andconditions the can be treated with the compounds and compositions of theinvention include, but are not limited to, cancer and neurodegenerativedisorders susceptible to treatment by inhibition of p97. Exemplaryneurodegenerative disorders include, but are not limited to, inclusionbody myopathy (IBM), Paget's disease of the bone (PDB), frontotemporaldementia (FTD) and amyotrophic lateral sclerosis (ALS).

Subjects having p97 mutations may also be treated with the compounds andcompositions according to the invention. Such p97 mutations may manifestsymptoms including but not limited to Parkinsonism, ataxia, cataracts,dilated cardiomyopathy, hepatic fibrosis, and hearing loss. Treatmentwith a compound or composition according to the invention may amelioratesuch symptoms.

In one aspect, provided is a compound having the structure of formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,        —N═N⁺═N⁻, an optionally substituted C₁-C₃ alkyl, an optionally        substituted C₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted        6-10 membered aryl, an optionally substituted 5-10 membered        heteroaryl, —S(O)₂R⁵, —OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or        S(Z)₅;    -   each of R⁵ or R⁶ is independently H, D, an optionally        substituted C₁-C₅ alkyl, an optionally substituted C₁-C₃ alkoxy,        or R⁵ and R⁶, together with the intervening atoms to which they        are attached, can form a 5-6 membered ring;    -   Z is a halo;    -   ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a        5-10 membered heterocyclyl;    -   R² is H, D, halo, cyano, or an optionally substituted C₁-C₃        alkyl;    -   m is 0, 1, 2, 3, or 4;    -   R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and        R³, together with the intervening atoms to which they are        attached, can form a 5-6 membered ring;    -   L¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—;        —NR⁵C(O)O—; —C(O)NR⁶—; —S(O)—; or —S(O)₂—;    -   X is CH or N;    -   Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;    -   L² is a bond, an optionally substituted C₁-C₅ alkyl, or an        optionally substituted 3-10 membered cycloalkyl;    -   A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl,        an optionally substituted 4-10 membered heterocyclyl, an        optionally substituted 5-10 membered heteroaryl, an optionally        substituted 6-10 membered aryl, or an optionally substituted 4-7        membered cycloalkyl;    -   each R¹⁰ independently is H, an optionally substituted C₁-C₃        alkyl, an optionally substituted 5-7 membered heteroaryl, or an        optionally substituted 6-10 membered aryl;    -   p is 0, 1, 2, 3, or 4; and    -   denotes a single or double bond;    -   wherein the compound is not:

In another aspect, provided is a pharmaceutical composition comprising acompound provided herein and at least one pharmaceutically acceptableexcipient or carrier.

In another aspect, provided is a method of inhibiting p97 in a subjectin need thereof, comprising administering to the subject atherapeutically effective amount of a compound of formula II or atherapeutically effective amount of a pharmaceutical compositioncomprising a compound of formula I and at least one pharmaceuticallyacceptable excipient or carrier:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,        —N═N⁺═N⁻, an optionally substituted C₁-C₃ alkyl, an optionally        substituted C₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted        6-10 membered aryl, an optionally substituted 5-10 membered        heteroaryl, —S(O)₂R⁵, —OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or        S(Z)₅;    -   each of R⁵ or R⁶ is independently H, D, an optionally        substituted C₁-C₅ alkyl, an optionally substituted C₁-C₃ alkoxy,        or R⁵ and R⁶, together with the intervening atoms to which they        are attached, can form a 5-6 membered ring;    -   Z is a halo;    -   ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a        5-10 membered heterocyclyl;    -   R² is H, D, halo, cyano, or an optionally substituted C₁-C₃        alkyl;    -   m is 0, 1, 2, 3, or 4;    -   R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and        R³, together with the intervening atoms to which they are        attached, can form a 5-6 membered ring;    -   L¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—;        —NR⁵C(O)O—; —C(O)NR⁶—; —S(O)—; or —S(O)₂—;    -   X is CH or N;    -   Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;    -   L² is a bond, an optionally substituted C₁-C₅ alkyl, or an        optionally substituted 3-10 membered cycloalkyl;    -   A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl,        an optionally substituted 4-10 membered heterocyclyl, an        optionally substituted 5-10 membered heteroaryl, an optionally        substituted 6-10 membered aryl, or an optionally substituted 4-7        membered cycloalkyl;    -   each R¹⁰ independently is H, an optionally substituted C₁-C₃        alkyl, an optionally substituted 5-7 membered heteroaryl, or an        optionally substituted 6-10 membered aryl;    -   p is 0, 1, 2, 3, or 4; and    -   denotes a single or double bond.

In another aspect, provided is a method of treating cancer or aneurodegenerative disorder susceptible to treatment by p97 inhibition ina subject in need thereof. The method comprises administering to thesubject a therapeutically effective amount of a compound of formula I ora therapeutically effective amount of a pharmaceutical compositioncomprising a compound of formula I and at least one pharmaceuticallyacceptable excipient or carrier:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,        —N═N⁺═N⁻, an optionally substituted C₁-C₃ alkyl, an optionally        substituted C₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted        6-10 membered aryl, an optionally substituted 5-10 membered        heteroaryl, —S(O)₂R⁵, —OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or        S(Z)₅;    -   each of R⁵ or R⁶ is independently H, D, an optionally        substituted C₁-C₅ alkyl, an optionally substituted C₁-C₃ alkoxy,        or R⁵ and R⁶, together with the intervening atoms to which they        are attached, can form a 5-6 membered ring;    -   Z is a halo;    -   ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a        5-10 membered heterocyclyl;    -   R² is H, D, halo, cyano, or an optionally substituted C₁-C₃        alkyl;    -   m is 0, 1, 2, 3, or 4;    -   R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and        R³, together with the intervening atoms to which they are        attached, can form a 5-6 membered ring    -   L¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—;        —NR⁵C(O)O—; —C(O)NR⁶—; —S(O)—; or —S(O)₂—;    -   X is CH or N;    -   Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;    -   L² is a bond, an optionally substituted C₁-C₅ alkyl, or an        optionally substituted 3-10 membered cycloalkyl;    -   A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl,        an optionally substituted 4-10 membered heterocyclyl, an        optionally substituted 5-10 membered heteroaryl, an optionally        substituted 6-10 membered aryl, or an optionally substituted 4-7        membered cycloalkyl;    -   each R¹⁰ independently is H, an optionally substituted C₁-C₃        alkyl, an optionally substituted 5-7 membered heteroaryl, or an        optionally substituted 6-10 membered aryl;    -   p is 0, 1, 2, 3, or 4; and    -   denotes a single or double bond.

The foregoing general description and following description of thedrawings and detailed description are exemplary and explanatory and areintended to provide further explanation of the invention as claimed.Other objects, advantages, and novel features will be readily apparentto those skilled in the art from the following brief description of thedrawings and detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of p97 inhibitors.

FIG. 2 shows the features of p97-associated disease.

FIG. 3 shows the structures and steric/electronic features of compoundsof the present disclosure.

DETAILED DESCRIPTION I. Compounds of the Disclosure

Compounds of the present disclosure include novel compounds with thefollowing core structure:

The core structure is substituted at one or more positions marked as *.

In some embodiments, the compounds of the present disclosure arerepresented by the following structure:

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is a H, D, halo, cyano, hydroxyl, nitro, or—N═N⁺═N⁻. In some embodiments, R¹ is an optionally substituted alkyl, anoptionally substituted alkoxy, an optionally substituted aryl, or anoptionally substituted heteroaryl. In some embodiments, R¹ is anoptionally substituted C₁-C₃ alkyl, an optionally substituted C₁-C₃alkoxy, an optionally substituted 6-10 membered aryl, or an optionallysubstituted 5-10 membered heteroaryl.

In some embodiments, R¹ is —C(O)NR⁵R⁶, —C(O)OR⁵, —S(O)₂NR⁵R⁶, or—S(O)₂R⁵, wherein each of R⁵ or R⁶ is independently H, D, an optionallysubstituted alkyl, or an optionally substituted alkoxy. In someembodiments, each of R⁵ or R⁶ is independently an optionally substitutedC₁-C₅ alkyl or an optionally substituted C₁-C₃ alkoxy. In someembodiments, each of R⁵ and R⁶, together with the intervening atoms towhich they are attached, can form a 5-6 membered ring.

In some embodiments, R¹ is-OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or S(Z)₅,wherein Z is a halo. In some embodiments, Z is preferably F.

In some embodiments, ring B is a 6-10 membered aryl, a 5-10 memberedheteroaryl, or a 5-10 membered heterocyclyl. In some embodiments, ring Bis a phenyl. In some embodiments, ring B is a 5-6 membered heteroaryl.In some embodiments, ring B is a pyridinyl.

In some embodiments, R¹ is preferably halo, cyano, N(O)₂, hydroxyl, or—C(O)NR⁵R⁶, wherein each of R⁵ or R⁶ is independently H, D, anoptionally substituted alkyl, or an optionally substituted alkoxy. Insome embodiments, each of R⁵ or R⁶ is independently an optionallysubstituted C₁-C₅ alkyl or an optionally substituted C₁-C₃ alkoxy. Insome embodiments, each of R⁵ and R⁶, together with the intervening atomsto which they are attached, can form a 5-6 membered ring.

In some embodiments, R² is H, D, halo, cyano, or an optionallysubstituted alkyl. In some embodiments, R² is an optionally substitutedC₁-C₃ alkyl.

In some embodiments, R³ is H, D, or an optionally substituted alkyl. Insome embodiments, R³ is H, D, or an optionally substituted C₁-C₃ alkyl.

In some embodiments, R² and R³, together with the intervening atoms towhich they are attached, can form a 5-6 membered ring.

In some embodiments, L¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—;—NR⁵C(O)NR⁶—; —NR⁵C(O)O—; —C(O)NR⁶—; —S(O)—; or —S(O)₂—; wherein each ofR⁵ or R⁶ is independently H, D, an optionally substituted alkyl, or anoptionally substituted alkoxy. In some embodiments, each of R⁵ or R⁶ isindependently an optionally substituted C₁-C₅ alkyl or an optionallysubstituted C₁-C₃ alkoxy. In some embodiments, each of R⁵ and R⁶,together with the intervening atoms to which they are attached, can forma 5-6 membered ring.

In some embodiments, L¹ and

are meta-substituted to one another on ring B. In some embodiments, R²is para-substituted to L¹ on ring B. In some embodiments, R² isortho-substituted to

on ring B.

In some embodiments, X is CH or N. In some embodiments, X is preferablyN.

In some embodiments, Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S. Insome embodiments, Y is preferably NH.

In some embodiments, L² is a bond, an optionally substituted alkyl, oran optionally substituted cycloalkyl. In some embodiments, L² is anoptionally substituted C₁-C₅ alkyl or an optionally substituted 3-10membered cycloalkyl. In some embodiments, L² is an optionallysubstituted C₁-C₃ alkyl. In some embodiments, L² is an optionallysubstituted C₂ alkyl.

In some embodiments, A is —NR¹⁰R¹⁰ or —C(O)OR¹⁰, wherein each R¹⁰independently is H, an optionally substituted alkyl, an optionallysubstituted heteroaryl, or an optionally substituted aryl. In someembodiments, each R¹⁰ independently is an optionally substituted C₁-C₃alkyl, an optionally substituted 5-7 membered heteroaryl, or anoptionally substituted 6-10 membered aryl.

In some embodiments, A is an optionally substituted alkyl, an optionallysubstituted heterocyclyl, an optionally substituted heteroaryl, anoptionally substituted aryl, or an optionally substituted cycloalkyl. Insome embodiments, A is an optionally substituted C₁-C₅ alkyl, anoptionally substituted 4-10 membered heterocyclyl, an optionallysubstituted 5-10 membered heteroaryl, an optionally substituted 6-10membered aryl, or an optionally substituted 4-7 membered cycloalkyl.

In some embodiments, A is a 4-10 membered heterocyclyl. In someembodiments, A is a 4-10 membered heterocyclyl, wherein one of the ringheteroatoms of A is N.

In some embodiments, A has the structure:

wherein each b is independently 0 or 1. In some embodiments, one b is 1and the remaining two b's are 0. In some embodiments, two b's are 1 andthe remaining b is 0. In some embodiments, all three b's are 1.

In some embodiments, A has the structure:

wherein each R³ is independently CH or N and M is an optionallysubstituted alkyl. In some embodiments, M is an optionally substitutedC₁-C₆ alkyl. In preferred embodiments, M is a C₁-C₃ alkyl.

In some embodiments, A has the structure:

wherein M is an optionally substituted alkyl. In some embodiments, M isan optionally substituted C₁-C₆ alkyl. In preferred embodiments, M is aC₁-C₃ alkyl.

In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0.In some embodiments, m is 1. In some embodiments, m is 2. In someembodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In someembodiments, p is 1. In some embodiments, p is 2.

denotes a single or double bond.

In some embodiments, the compounds of the present disclosure are not

In some embodiments, the compounds of the present disclosure have thestructure of formula III

wherein the remaining variables are defined as above.

In some embodiments, the compounds of the present disclosure areselected from the compounds of Table 1 or a pharmaceutically acceptablesalt thereof. It should be noted that the moieties of the compounds ofTable 1 fall within the scope of compounds of Formulae (I) and (II). Thepresent disclosure includes embodiments where one or more of thevariable moieties of Formulae (I) or (II) are represented by theequivalent moiety of one or more of the compounds of Table 1 withoutrequiring the other specific moieties of the same compound of Table 1.

TABLE 1

II. Methods of Treatment

In some embodiments, the compounds of the present disclosure have anADP-Glo™ IC₅₀ value of less than about 25 μM, meaning that at aconcentration of 25 μM, the compounds inhibit expression of p97 by half.In other embodiments, the compounds of the invention have an ADP-Glo™IC₅₀ value of less than about 50 μM, less than about 45 μM, less thanabout 40 μM, less than about 35 μM, less than about 30 μM, less thanabout 25 μM, less than about 20 μM, less than about 15 μM, less thanabout 10 μM, or less than about 5 μM. ADP-Glo™ (Promega Corp.) is abioluminescent, homogeneous assay that measures ADP formed from abiochemical reactions. Because of its high sensitivity, the assay issuitable for monitoring enzyme activities at very early substrateconversions requiring very low amount of enzymes. This is critical sinceinhibitor potency has to be demonstrated at the cellular level where ATPis present at millimolar concentrations.

One aspect of the present invention includes methods of inhibiting p97in a subject in need thereof. In some embodiments, the treatment of thesubject in need thereof comprises administering a compound of thepresent disclosure (e.g., a compound of Formula (I), (II) or Table 1) tothe subject suspected of, or already suffering from elevated activity ofp97, in an amount sufficient to cure, or at least partially arrest, thesymptoms of elevated activity of p97. As such, some embodiments of thedisclosure include methods of treating a subject in need thereof who issuffering from, suspected as having, or at risk of having elevatedactivity of p97.

Another aspect of the present invention includes methods of treatingcancers or neurodegenerative disorders susceptible to treatment by p97inhibition in a subject diagnosed as having, suspected as having, or atrisk of having cancer or a neurodegenerative disorder susceptible totreatment by p97 inhibition. As such, some embodiments of the disclosureinclude methods of treating a subject in need thereof who is sufferingfrom, suspected as having, or at risk of having cancer or aneurodegenerative disorder susceptible to treatment by p97 inhibition.In some embodiments, the treatment of the subject in need thereofcomprises administering a compound of the present disclosure (e.g., acompound of Formula (I), (II) or Table 1) to the subject suspected of,or already suffering from cancer or a neurodegenerative disordersusceptible to treatment by p97 inhibition, in an amount sufficient tocure, or at least partially arrest, the symptoms of the disease,including its complications and intermediate pathological phenotypes indevelopment of the disease.

In some embodiments, cancers susceptible to treatment by p97 inhibitioninclude but are not limited to solid tumor cancers, non-small cell lungcarcinoma, multiple myeloma, or mantle cell lymphoma. In someembodiments, cancers susceptible to treatment by p97 inhibition includea solid tumor. See Valle et al., “Critical Role of VCP/p97 in thePathogenesis and Progression of Non-Small Cell Lung Carcinoma,” PlosOne,6(12): e29073 (2011) and Deshaies et al., “Proteotoxic crisis, theubiquitin-proteasome system, and cancer therapy,” BMC Biology, 12(94)(2014).

In some embodiments, neurodegenerative disorders susceptible totreatment by p97 inhibition include but are not limited to inclusionbody myopathy (IBM), Paget's disease of the bone (PDB), frontotemporaldementia (FTD) and amyotrophic lateral sclerosis (ALS)).Neurodegenerative disorders also include subjects having p97 mutations,and symptoms manifesting as, for example, Parkinsonism, ataxia,cataracts, dilated cardiomyopathy, hepatic fibrosis, and hearing loss.

The compound may be included in a pharmaceutical formulation such asthose disclosed herein, and may be administered in any pharmaceuticallyacceptable manner, including methods of administration described herein.

The compounds useful in the methods of the present invention isadministered to a mammal in an amount effective in treating orpreventing elevated activity of p97, cancers susceptible to treatment byp97 inhibition, or neurodegenerative disorders susceptible to treatmentby p97 inhibition. The therapeutically effective amount can bedetermined by methods known in the art.

An effective amount of a compound useful in the methods of the presentinvention, for example in a pharmaceutical composition, may beadministered to a mammal in need thereof by any of a number ofwell-known methods for administering pharmaceutical compounds. Thecompound may be administered systemically or locally. In one embodiment,the compound is administered intravenously. For example, the compoundsuseful in the methods of the present technology may be administered viarapid intravenous bolus injection. In some embodiments, the compound isadministered as a constant rate intravenous infusion. The compound mayalso be administered orally, topically, intranasally, intramuscularly,subcutaneously, or transdermally. Other routes of administration includeintracerebroventricularly or intrathecally. Intracerebroventiculatlyrefers to administration into the ventricular system of the brain.Intrathecally refers to administration into the space under thearachnoid membrane of the spinal cord.

The compounds useful in the methods of the present technology may alsobe administered to mammals by sustained or controlledrelease, as isknown in the art. Sustained release administration is a method of drugdelivery to achieve a certain level of the drug over a particular periodof time. The level typically is measured by serum or plasmaconcentration.

In one preferred embodiment, the compounds are administered orally. Inone preferred embodiment, the compounds are administered intravenously.In one preferred embodiment, the compounds are administered at less than1 gram per day.

III. Pharmaceutical Formulations

For oral administration, liquid or solid dose formulations may be used.Some examples of oral dosage formulations include tablets, gelatincapsules, pills, troches, elixirs, suspensions, syrups, wafers, chewinggum and the like. The compounds can be mixed with a suitablepharmaceutical carrier (vehicle) or excipient as understood bypractitioners in the art. Examples of carriers and excipients includestarch, milk, sugar, certain types of clay, gelatin, lactic acid,stearic acid or salts thereof, including magnesium or calcium stearate,talc, vegetable fats or oils, gums and glycols.

For systemic, intracerebroventricular, intrathecal, topical, intranasal,subcutaneous, or transdermal administration, formulations of thecompounds useful in the methods of the present technology may utilizeconventional diluents, carriers, or excipients etc., such as are knownin the art can be employed to deliver the compounds. For example, theformulations may comprise one or more of the following: a stabilizer, asurfactant (such as a nonionic, ionic, anionic, or zwitterionicsurfactant), and optionally a salt and/or a buffering agent. Thecompound may be delivered in the form of a solution or in areconstituted lyophilized form.

In some embodiments, the stabilizer may, for example, be an amino acid,such as for instance, glycine; or an oligosaccharide, such as forexample, sucrose, tetralose, lactose or a dextran. Alternatively, thestabilizer may be a sugar alcohol, such as for instance, mannitol; or acombination thereof. In some embodiments, the stabilizer or combinationof stabilizers constitutes from about 0.1% to about 10% weight forweight of the compound.

In some embodiments, the surfactant is a nonionic surfactant, such as apolysorbate. Some examples of suitable surfactants include polysorbates(e.g., Tween20, Tween80); a polyethylene glycol or a polyoxyethylenepolyoxypropylene glycol, such as Pluronic F-68 at from about 0.001%(w/v) to about 10% (w/v).

A salt or buffering agent may be any salt or buffering agent, such asfor example, sodium chloride, or sodium/potassium phosphate,respectively. In certain embodiments, the buffering agent maintains thepH of the pharmaceutical composition in the range of about 5.5 to about7.5. The salt and/or buffering agent is also useful to maintain theosmolality at a level suitable for administration to a human or ananimal. In some embodiments, the salt or buffering agent is present at aroughly isotonic concentration of about 150 mM to about 300 mM.

The formulations of the compounds useful in the methods of the presenttechnology may additionally comprise one or more conventional additives.Some examples of such additives include a solubilizer such as, forexample, glycerol; an antioxidant such as for example, benzalkoniumchloride (a mixture of quaternary ammonium compounds, known as “quats”),benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such asfor example a morphine derivative; or an isotonic agent etc., such asdescribed above. As a further precaution against oxidation or otherspoilage, the pharmaceutical compositions may be stored under nitrogengas in vials sealed with impermeable stoppers.

The mammal can be any mammal, including, for example, farm animals, suchas sheep, pigs, cows, and horses; pet animals, such as dogs and cats;laboratory animals, such as rats, mice and rabbits. In one embodiment,the mammal is a human.

IV. Combination Therapy

In some embodiments, the compounds of the present disclosure may becombined with one or more additional therapies for the prevention ortreatment of a disease or condition amenable to treatment by inhibitionof p97. Additional therapeutic agents or active agents include, but arenot limited to, alkylating agents, nitrosoureas, antimetabolites,antitumor antibiotics, plant vinca alkaloids, and steroid hormones.

The multiple therapeutic agents may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents.

In one embodiment, the compounds of the present disclosure can becombined with proteosome inhibitors. In another embodiment, thecompounds of the present disclosure can be combined with otheranti-cancer agents. In another embodiment, the compounds of the presentdisclosure can be combined with heat shock protein (HSP) inhibitors. Inanother embodiment, the compounds of the present disclosure can becombined with two or more of proteasome inhibitors, HSP inhibitors, andother anti-cancer agents.

V. Definitions

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely”, “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As used herein, the term “about” will be understood by persons ofordinary skill in the art and will vary to some extent depending uponthe context in which it is used. If there are uses of the term which arenot clear to persons of ordinary skill in the art given the context inwhich it is used, “about” will mean up to plus or minus 10% of theparticular term.

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium. Hence, isotopically labeled compounds are within the scope ofthe invention.

In general, “substituted” refers to an organic group as defined below(e.g., an alkyl group) in which one or more bonds to a hydrogen atomcontained therein are replaced by a bond to non-hydrogen or non-carbonatoms. Substituted groups also include groups in which one or more bondsto a carbon(s) or hydrogen(s) atom are replaced by one or more bonds,including double or triple bonds, to a heteroatom. Thus, a substitutedgroup will be substituted with one or more substituents, unlessotherwise specified. In some embodiments, a substituted group issubstituted with 1, 2, 3, 4, 5, or 6 substituents. Examples ofsubstituent groups include: halogens (i.e., F, Cl, Br, and I);hydroxyls; alkoxy, alkenoxy, alkynoxy, aryloxy, aralkyloxy,heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo);carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines;aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls;sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones;azides; amides; ureas; amidines; guanidines; enamines; imides;isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitrogroups; nitriles (i.e., CN); and the like.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and fused ringsystems in which a bond to a hydrogen atom is replaced with a bond to acarbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups may also be substituted with substituted orunsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

Alkyl groups include straight chain and branched alkyl groups havingfrom 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or,in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkylgroups further include cycloalkyl groups as defined below. Examples ofstraight chain alkyl groups include those with from 1 to 8 carbon atomssuch as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl,and n-octyl groups. Examples of branched alkyl groups include, but arenot limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl,isopentyl, and 2,2-dimethylpropyl groups. Representative substitutedalkyl groups may be substituted one or more times with substituents suchas those listed above.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8ring members, whereas in other embodiments the number of ring carbonatoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups furtherinclude mono-, bicyclic and polycyclic ring systems, such as, forexample bridged cycloalkyl groups as described below, and fused rings,such as, but not limited to, decalinyl, and the like. In someembodiments, polycyclic cycloalkyl groups have three rings. Substitutedcycloalkyl groups may be substituted one or more times with,non-hydrogen and non-carbon groups as defined above. However,substituted cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-2,5- or 2,6-disubstituted cyclohexyl groups, which may besubstituted with substituents such as those listed above.

Bridged cycloalkyl groups are cycloalkyl groups in which two or morehydrogen atoms are replaced by an alkylene bridge, wherein the bridgecan contain 2 to 6 carbon atoms if two hydrogen atoms are located on thesame carbon atom, or 1 to 5 carbon atoms, if the two hydrogen atoms arelocated on adjacent carbon atoms, or 2 to 4 carbon atoms if the twohydrogen atoms are located on carbon atoms separated by 1 or 2 carbonatoms. Bridged cycloalkyl groups can be bicyclic, such as, for examplebicyclo[2.1.1]hexane, or tricyclic, such as, for example, adamantyl.Representative bridged cycloalkyl groups include bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decanyl,adamantyl, noradamantyl, bornyl, or norbornyl groups. Substitutedbridged cycloalkyl groups may be substituted one or more times withnon-hydrogen and non-carbon groups as defined above. Representativesubstituted bridged cycloalkyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, mono-, di- ortri-substituted adamantyl groups, which may be substituted withsubstituents such as those listed above.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Aryl groups include monocyclic, bicyclic and polycyclicring systems. Thus, aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenylenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenyl, anthracenyl,indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments,aryl groups contain 6-14 carbons, and in others from 6 to 12 or even6-10 carbon atoms in the ring portions of the groups. Although thephrase “aryl groups” includes groups containing fused rings, such asfused aromatic-aliphatic ring systems (e.g., indanyl,tetrahydronaphthyl, and the like), it does not include aryl groups thathave other groups, such as alkyl or halo groups, bonded to one of thering members. Rather, groups such as tolyl are referred to assubstituted aryl groups. Representative substituted aryl groups may bemono-substituted or substituted more than once. For example,monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-,5-, or 6-substituted phenyl or naphthyl groups, which may be substitutedwith substituents such as those listed above.

Heterocyclyl groups include aromatic (also referred to as heteroaryl)and non-aromatic ring compounds containing 3 or more ring members, ofwhich one or more is a heteroatom such as, but not limited to, N, O, andS. In some embodiments, heterocyclyl groups include 3 to 20 ringmembers, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3to 15 ring members. Heterocyclyl groups encompass unsaturated, partiallysaturated and saturated ring systems, such as, for example, imidazolyl,imidazolinyl and imidazolidinyl groups. The phrase “heterocyclyl group”includes fused ring species including those comprising fused aromaticand non-aromatic groups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. However, the phrase does notinclude heterocyclyl groups that have other groups, such as alkyl, oxoor halo groups, bonded to one of the ring members. Rather, these arereferred to as “substituted heterocyclyl groups”. Heterocyclyl groupsinclude, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl,imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl,thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane,dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl,dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl,isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl,benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl,benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl(azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substitutedor substituted more than once, such as, but not limited to, pyridyl ormorpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, ordisubstituted with various substituents such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl(pyrrolopyridyl), indazolyl, benzimidazolyl, imidazopyridyl(azabenzimidazolyl), pyrazolopyridyl, triazolopyridyl, benzotriazolyl,benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl,isoxazolopyridyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl,and quinazolinyl groups. Although the phrase “heteroaryl groups”includes fused ring compounds such as indolyl and 2,3-dihydro indolyl,the phrase does not include heteroaryl groups that have other groupsbonded to one of the ring members, such as alkyl groups. Rather,heteroaryl groups with such substitution are referred to as “substitutedheteroaryl groups.” Representative substituted heteroaryl groups may besubstituted one or more times with various substituents such as thoselisted above.

Groups described herein having two or more points of attachment (i.e.,divalent, trivalent, or polyvalent) within the compound of the inventionare designated by use of the suffix, “ene.” For example, divalent alkylgroups are alkylene groups, divalent aryl groups are arylene groups,divalent heteroaryl groups are divalent heteroarylene groups, and soforth. Substituted groups having a single point of attachment to thecompound of the invention are not referred to using the “ene”designation. Thus, e.g., chloroethyl is not referred to herein aschloroethylene.

Alkoxy groups are hydroxyl groups (—OH) in which the bond to thehydrogen atom is replaced by a bond to a carbon atom of a substituted orunsubstituted alkyl group as defined above. Examples of linear alkoxygroups include but are not limited to methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, and the like. Examples of branched alkoxy groupsinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groupsinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. Representative substitutedalkoxy groups may be substituted one or more times with substituentssuch as those listed above.

The term “amine” (or “amino”) as used herein refers to —NHR⁴ and —NR⁵R⁶groups, wherein R⁴, R⁵ and R⁶ are independently hydrogen, or asubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl,aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Insome embodiments, the amine is NH₂, methylamino, dimethylamino,ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, orbenzylamino.

The term “amide” refers to a-NR′R″C(O)— group wherein R′ and R″ eachindependently refer to a hydrogen, (C₁-C₅)alkyl, or (C₃-C₆)aryl.

The term “nitrile or cyano” can be used interchangeably and refer to a—CN group which is bound to a carbon atom of a heteroaryl ring, arylring and a heterocycloalkyl ring.

The substituent-CO₂H, may be replaced with bioisosteric replacementssuch as:

and the like, wherein R has the same definition as R′ and R″ as definedherein. See, e.g., THE PRACTICE OF MEDICINAL CHEMISTRY (Academic Press:New York, 1996), at page 203.

Those of skill in the art will appreciate that compounds of theinvention may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism and/or optical isomerism. As the formuladrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, optical isomeric orgeometric isomeric forms, it should be understood that the inventionencompasses any tautomeric, conformational isomeric, optical isomericand/or geometric isomeric forms of the compounds having one or more ofthe utilities described herein, as well as mixtures of these variousdifferent forms.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism, and alltautomers of compounds as described herein are within the scope of thepresent invention.

Stereoisomers of compounds, also known as “optical isomers,” include allchiral, diastereomeric, and racemic forms of a structure, unless thespecific stereochemistry is expressly indicated. Thus, compounds used inthe present invention include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions. Bothracemic and diastereomeric mixtures, as well as the individual opticalisomers can be isolated or synthesized so as to be substantially free oftheir enantiomeric or diastereomeric partners, and these are all withinthe scope of the invention.

By “pharmaceutically acceptable” is meant a material that is notbiologically or otherwise undesirable, i.e., the material may beincorporated into a pharmaceutical composition administered to a patientwithout causing any undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. When the term “pharmaceutically acceptable” isused to refer to a pharmaceutical carrier or excipient, it is impliedthat the carrier or excipient has met the required standards oftoxicological and manufacturing testing or that it is included on theInactive Ingredient Guide prepared by the U.S. and Drug administration.

By “patient” is meant any animal for which treatment is desirable.Patients may be mammals, and typically, as used herein, a patient is ahuman individual.

The term “pharmaceutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds of the present inventionwhich are water or oil-soluble or dispersible; which are suitable fortreatment of diseases without undue toxicity, irritation, andallergic-response; which are commensurate with a reasonable benefit/riskratio; and which are effective for their intended use. The salts can beprepared during the final isolation and purification of the compounds orseparately by reacting the appropriate compound in the form of the freebase with a suitable acid. Representative acid addition salts includeacetate, adipate, alginate, L-ascorbate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, butyrate, camphorate,camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate,glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate,DL-mandelate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), andundecanoate. Also, basic groups in the compounds of the presentinvention can be quaternized with methyl, ethyl, propyl, and butylchlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamylsulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, andiodides; and benzyl and phenethyl bromides. Examples of acids which canbe employed to form pharmaceutically acceptable addition salts includeinorganic acids such as hydrochloric, hydrobromic, sulfuric, andphosphoric, and organic acids such as oxalic, maleic, succinic, andcitric. Salts can also be formed by coordination of the compounds withan alkali metal or alkaline earth ion. Hence, the present inventioncontemplates sodium, potassium, magnesium, and calcium salts of thecompounds of the compounds of the present invention and the like.

The term “solvates” is used in its broadest sense. For example, the termsolvates includes hydrates formed when a compound of the presentinvention contains one or more bound water molecules.

Certain ranges are presented herein with numerical values being precededby the term “about”. The term “about” is used herein to provide literalsupport for the exact number that it precedes, as well as a number thatis near to or approximately the number that the term precedes. Indetermining whether a number is near to or approximately a specificallyrecited number, the near or approximating unrecited number may be anumber which, in the context in which it is presented, provides thesubstantial equivalent of the specifically recited number.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

This disclosure is not limited to particular embodiments described, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting, since the scope ofthe present invention will be limited only by the appended claims.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

VI. Working Examples

The present technology is further illustrated by the following examples,which should not be construed as limiting in any way.

General information. All non-aqueous reactions were carried out under anitrogen atmosphere in oven- or flame-dried glassware unless otherwisenoted. Anhydrous tetrahydrofuran and diethyl ether were distilled fromsodium benzophenone ketyl; anhydrous dichloromethane and toluene weredistilled from CaH₂; alternatively, the same solvents were obtained froma solvent purification system using alumina columns. All other solventsand reagents were used as obtained from commercial sources withoutfurther purification unless noted. Reactions were monitored via TLCusing 250 pm pre-coated silica gel 60 F₂₅₄ plates, which were visualizedwith 254 nm and/or 365 nm UV light and by staining with KMnO₄ (1.5 gKMnO₄, 10 g K₂CO₃, and 1.25 mL 10% NaOH in 200 mL water), ceriummolybdate (0.5 g Ce(NH₄)₂(NO₃)₆, 12 g (NH₄)₆Mo₇O₂₄.4H₂O, and 28 mL conc.H₂SO₄ in 235 mL water), or vanillin (6 g vanillin and 1.5 mL conc. H₂SO₄in 100 mL EtOH). Flash chromatography was performed with SiliCyclesilica gel 60 (230-400 mesh) or with ISCO MPLC. ¹H and ¹³C NMR spectrawere recorded on Bruker Avance 300, 400, or 500 MHz spectrometers, usingthe residual solvent as an internal standard. IR spectra were obtainedon a Smiths IdentifyIR or PerkinElmer Spectrum 100. IRMS data wereobtained on a Thermo Scientific Exactive IRMS coupled to a ThermoScientific Accela HPLC system using a 2.1×50 mm 3.5 pm Waters XTerra Ciscolumn eluting with MeCN/H₂O containing 0.1% formic acid. Purity ofcompounds was assessed using the same HPLC system with either the PDA oran Agilent 385 ELSD. All final screening samples passed QC based on >95%purity by LC/MS/ELSD analysis.

General Synthetic Methods

The compounds of the present disclosure can be prepared using thefollowing general methods and procedures. The starting materials for thefollowing reactions are generally known compounds or can be prepared byknown procedures or obvious modifications thereof. For example, many ofthe starting materials are available from commercial suppliers such asAldrich Chemical Co. (Milwaukee, Wis., USA), Bachem (Torrance, Calif.,USA), Emka-Chemce or Sigma (St. Louis, Mo., USA). Others may be preparedby procedures, or obvious modifications thereof, described in standardreference texts such as Fieser and Fieser's Reagents for OrganicSynthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistryof Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier SciencePublishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, andSons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons,5^(th) Edition, 2001), and Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989).

More specifically, compounds provided herein can be synthesized as shownbelow (see Schemes 1 and 2), and following adaptations of the methodsshown below and/or methods known to a skilled artisan and/or by usingdifferent commercially available starting materials.

Synthesis of tert-Butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate (17)

A solution of benzyl 4-oxopiperidine-1-carboxylate (1.54 g, 6.61 mmol),2-(4-isopropylpiperazin-1-yl)ethan-1-amine (1.03 g, 6.01 mmol, Tapia,I.; Alonso-Cires, L.; Lopez-Tudanca, P. L.; Mosquera, R.; Labeaga, L.;Innerarity, A.; Orjales, A. J. Med Chem. 1999, 42, 2870-2880), and AcOH(52.2 μL, 0.902 mmol) in anhydrous CH₂Cl₂ (100 mL) was treated withNaBH(OAc)₃ (1.94 g, 9.02 mmol). The reaction mixture was stirred at roomtemperature overnight, diluted with CH₂Cl₂ (100 mL), washed with sat.NaHCO₃, brine, dried (Na₂SO₄), and evaporated to give benzyl4-((2-(4-isopropylpiperazin-1-yl)ethyl)amino)piperidine-1-carboxylate(2.33 g, quant.) as a pale yellow oil that was used without furtherpurification: ¹H NMR (300 MHz, CDCl₃) δ 7.37-7.32 (m, 5H), 5.12 (s, 2H),4.11 (app d, J=10.3 Hz, 2H), 2.88 (app t, J=11.8 Hz, 2H), 2.74-2.47 (m,14H), 1.85 (d, J=12.6 Hz, 2H), 1.35-1.22 (m, 2H), 1.06 (d, J=6.5 Hz,6H).

A solution of benzyl4-((2-(4-isopropylpiperazin-1-yl)ethyl)amino)piperidine-1-carboxylate(8.34 g, 21.5 mmol) in anhydrous CH₂Cl₂ (350 mL) was treated with Boc₂O(8.43 g, 38.6 mmol). The reaction mixture was stirred at roomtemperature overnight, diluted with CH₂Cl₂ (350 mL), washed with sat.NaHCO₃, brine, dried (Na₂SO₄), evaporated, and purified bychromatography on SiO₂ (2% MeOH/CH₂Cl₂ with 1% TEA) followed bychromatography on basic Al₂O₃ (0 to 1% MeOH/CH₂Cl₂) to give benzyl4-((tert-butoxycarbonyl)(2-(4-isopropylpiperazin-1-yl)ethyl)amino)piperidine-1-carboxylate(8.08 g, 77%) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.29(m, 5H), 5.11 (s, 2H), 4.26 (bs, 2H), 4.09 (bs, 1H), 3.17 (bs, 2H), 2.78(bs, 2H), 2.66-2.40 (m, 11H), 1.65-1.56 (m, 4H), 1.45 (s, 9H), 1.03 (d,J=6.5 Hz, 6H).

A solution of benzyl4-((tert-butoxycarbonyl)(2-(4-isopropylpiperazin-1-yl)ethyl)amino)piperidine-1-carboxylate(2.54 g, 5.20 mmol) in THE (120 mL) was treated with 10% Pd/C (0.512 g,0.480 mmol). The reaction mixture was subjected to 3 cycles ofvacuum/hydrogen backfill and stirred for 3 d under a hydrogenatmosphere. The reaction mixture was filtered through a pad of Celite©and concentrated to give tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate (17, 1.80g, 98%) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 4.01 (bs, 1H),3.23 (app t, J=5.4 Hz, 2H), 3.11 (d, J=11.8 Hz, 2H), 2.68-2.43 (m, 13H),1.68-1.65 (m, 2H), 1.60-1.52 (m, 2H), 1.46 (s, 9H), 1.04 (d, J=6.5 Hz,6H); HRMS (ESI) m/z calcd for C₁₉H₃₉O₂N₄ [M+H]⁺ 355.3068, found355.3067.

Synthesis ofN-(2-(4-Isopropylpiperazin-1-yl)ethyl)-1-(3-(5-(trifluoromethyl)-1H-indol-2-yl)phenyl)piperidin-4-amine(12)

A solution of 3-bromoiodobenzene (32, 0.284 g, 1.00 mmol),5-trifluoromethylindole (0.155 g, 0.840 mmol; Walkington, A.; Gray, M.;Hossner, F.; Kitteringham, J.; Voyle, M. Synth. Commun. 2003, 33,2229-2233), Pd(OAc)₂ (10 mg, 0.04 mmol), bis(diphenylphosphino)methane(17 mg, 0.040 mmol), and KOAc (0.249 g, 2.51 mmol) in deoxygenated water(2 mL) was heated at 110° C. for 24 h, cooled to room temperature,diluted with EtOAc (10 mL) and 1 N HCl (5 mL), and extracted with EtOAc(2×10 mL). The combined organic layers were dried (MgSO₄), concentrated,and purified by chromatography on SiO₂ (10% EtOAc/petroleum ether). Theresidue was recrystallized (hexanes/CH₂Cl₂) to give2-(3-bromophenyl)-5-(trifluoromethyl)-1H-indole (16, 139 mg, 49%) as acolorless solid: ¹H NMR (400 MHz, CDCl₃) δ 8.48 (bs, 1H), 7.92 (s, 1H),7.79 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.46-7.00(m, 2H), 7.36-7.27 (m, 1H), 6.88 (d, J=1.6 Hz, 1H).

A solution of 2-(3-bromophenyl)-5-(trifluoromethyl)-1H-indole (16, 85mg, 0.25 mmol), LiHMDS (0.10 g, 0.60 mmol), Pd₂(dba)₃ (5 mg, 0.005mmol), and CyJohnPhos (7 mg, 0.02 mmol) in anhydrous THF was treatedwith tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate (17, 0.107g, 0.300 mmol). The reaction mixture was heated at 55° C. overnight,cooled to room temperature, diluted with sat. NaHCO₃, and extracted withCH₂Cl₂ (3×). The combined organic layers were washed with brine, dried(Na₂SO₄), concentrated, and purified by chromatography on SiO₂ (2%MeOH/CH₂Cl₂ with 0.1% TEA) followed by chromatography on basicAl₂O₃(CH₂Cl₂) to give tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(trifluoromethyl)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(35 mg, 0.057 mmol, 23%) as a foam: IR (ATR) 3234, 2963, 2930, 2812,1685, 1601, 1465, 1330, 1151, 1110, 1051 cm¹; ¹H NMR (400 MHz, CDCl₃) δ9.19 (s, 1H), 7.89 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.38 (dd, J=8.4, 1.2Hz, 1H), 7.31 (t, J=8.0 Hz, 1H), 7.23 (bs, 1H), 7.16 (bd, J=7.6 Hz, 1H),6.90 (dd, J=7.8, 1.0 Hz, 1H), 6.84 (d, J=1.2 Hz, 1H), 4.12 (bs, 1H),3.79 (bd, J=4.0 Hz, 2H), 3.22 (bs, 2H), 2.82-2.47 (m, 13H), 1.76-1.75(m, 3H), 1.48 (s, 9H), 1.25-1.22 (m, 1H), 1.11 (d, J=6.0 Hz, 6H); HRMS(ESI) m/z calcd for C₃₄H₄₇O₂N₅F₃ [M+H]⁺ 614.3676, found 614.3678.

A solution of TFA (0.43 mL, 5.7 mmol) and triethylsilane (92 μL, 0.57mmol) in CH₂Cl₂ (1 mL) was added to a solution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(trifluoromethyl)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(35 mg, 0.057 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture was stirredunder an atmosphere of N₂ at room temperature for 1 h, concentrated,diluted with sat. NaHCO₃, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (Na₂SO₄), concentrated, andpurified by chromatography on SiO₂ (7 to 9% MeOH/CH₂Cl₂ with 0.1% TEA)followed by chromatography on basic Al₂O₃ (0 to 9% MeOH/CH₂Cl₂) to giveN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-(trifluoromethyl)-1H-indol-2-yl)phenyl)piperidin-4-amine(12, 17 mg, 0.033 mmol, 58%) as a yellow oil: ¹H NMR (500 MHz, CDCl₃) δ8.83 (s, 1H), 7.89 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.40 (dd, J=8.5, 1.0Hz, 1H), 7.33-7.30 (m, 1H), 7.22 (app s, 1H), 7.11 (d, J=7.5 Hz, 1H),6.93 (dd, J=8.3, 2.3 Hz, 1H), 6.84 (d, J=1.5 Hz, 1H), 3.74 (app d,J=12.5 Hz, 2H), 2.85 (td, J=12.0, 1.8 Hz, 2H), 2.78 (t, J=6.3 Hz, 2H),2.68-2.49 (m, 13H), 2.01 (bd, J=12.0 Hz, 2H), 1.54 (qd, J=11.6, 3.1 Hz,2H), 1.05 (d, J=6.5 Hz, 6H); ¹³C NMR (125 MHz, CDCl₃) δ 152.2, 140.6,138.1, 132.7, 129.9, 129.3, 128.7, 125.5 (q, J_(CF)=271.0 Hz), 122.7 (q,J_(CF)=31.6 Hz), 118.9 (q, J_(CF)=3.4 Hz), 118.3 (q, J_(CF)=4.2 Hz),116.5, 113.6, 111.2, 100.5, 58.1, 55.2, 54.6, 53.7, 48.9, 48.6, 43.6,32.7, 18.8; ¹⁹F NMR (376 MHz, CDCl₃) δ −60.4; HRMS (ESI) m/z calcd forC₂₉H₃₉N₅F₃ [M+H]⁺ 514.3152, found 514.3154.

Synthesis of1-{3-[5-(Pentafluoro-λ⁶-sulfanyl)-1H-indol-2-yl]phenyl}-N-{2-[4-(propan-2-yl)piperazin-1-yl]ethyl}piperidin-4-amine(13)

A suspension of 1-bromo-3-(dimethoxymethyl)benzene (18, 0.19 g, 0.82mmol, Kumar et al., Tetrahedron Lett., 46: 8319-8323 (2005)), 17 (0.32g, 0.90 mmol) and K₃PO₄ (0.27 g, 1.2 mmol) in dry dioxane (2.5 mL) wasdegassed for 40 min by bubbling argon, then Pd₂(dba)₃ (8 mg, 0.008 mmol)and CyJohnPhos (12 mg, 0.032 mmol) were added. The flask was sealed andthe reaction mixture was heated at 110° C. for 10 h, diluted with sat.NaHCO₃ and extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried (Na₂SO₄), and concentrated. The residue wasdissolved in acetone (27 mL) and H₂O (3 mL) and treated with TsOH.H₂O(0.48 g, 2.5 mmol) at rt for 3 h, then diluted with sat. Na₂CO₃ andextracted with EtOAc (3×). The combined organic layers were washed withbrine, dried (Na₂SO₄), and concentrated. The residue was purified bychromatography on SiO₂ (95:5 to 85:15 CH₂Cl₂/MeOH) to give tert-butyl(1-(3-formylphenyl)piperidin-4-yl)(2-(4-isopropylpiperazin-1-yl)ethyl)carbamate(19, 0.32 g, 0.70 mmol, 85% for two steps) as a pale yellow viscous oil:IR (ATR) 2961, 2931, 2808, 1685, 1595, 1450, 1365, 1175, 1145, 776 cm⁻¹;¹H NMR (500 MHz, CD₂Cl₂) δ 9.97 (s, 1H), 7.44 (t, J=7.9 Hz, 2H), 7.32(d, J=7.4 Hz, 1H), 7.23 (dd, J=8.2, 2.4 Hz, 1H), 4.09 (t, J=1.9 Hz, 1H),3.87 (d, J=12.5 Hz, 2H), 3.23 (s, 2H), 2.88 (t, J=11.6 Hz, 2H),2.70-2.45 (m, 11H), 1.90-1.80 (m, 4H), 1.48 (s, 9H), 1.06 (d, J=6.5 Hz,6H); ¹³C NMR (125 MHz, CD₂Cl₂) δ 192.6, 155.1, 151.7, 137.5, 129.7,122.0, 120.9, 115.4, 79.3, 58.3, 54.5, 49.1, 48.5, 40.6, 29.9, 28.2,18.2; HRMS (ESI) m/z calcd for C₂₆H₄₃O₃N₄ [M+H]⁺ 459.3330, found459.3329.

A solution of 1-nitro-4-(pentafluoro-λ⁶-sulfanyl)benzene (20, 1.0 g, 4.0mmol) and ((chloromethyl)sulfonyl)benzene (21, 0.77 g, 4.0 mmol) in DMF(4.0 mL) was added dropwise to a solution of t-BuOK (1.6 g, 14 mmol) inDMF (10 mL) at −30° C. The reaction mixture was stirred for 30 min at−30° C., quenched by addition of aq HCl (30 mL, 1 M), and extracted withCH₂Cl₂ (3×). The combined organic layers were washed with brine, dried(Na₂SO₄), and concentrated. The crude residue was purified bychromatography on SiO₂ (75:25 hexanes/EtOAc) to affordpentafluoro(4-nitro-3-((phenylsulfonyl)methyl)phenyl)-k⁶-sulfane)Iakobson, G.; Posta, M.; Beier, P. Synlett 2013; 24, 855-859) (1.4 g,3.4 mmol, 86%) as a pale yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.12(d, J=8.9 Hz, 1H), 7.95 (dd, J=8.9, 2.3 Hz, 1H), 7.74-7.69 (m, 4H), 7.56(t, J=7.8 Hz, 2H), 4.98 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 155.8(quintuplet, J_(CF)=19.7), 150.6, 137.4, 134.6, 131.91, 131.86, 131.82,129.6, 128.4, 127.97, 127.93, 127.88, 126.1, 124.5, 58.4.

A suspension ofpentafluoro(4-nitro-3-((phenylsulfonyl)methyl)phenyl)-λ⁶-sulfane (1.4 g,3.5 mmol) and 10% Pd/C (0.11 g, 0.10 mmol) in EtOH (100 mL) was treatedwith H₂ (balloon, 1 atm) at room temperature for 4 h. The mixture wasfiltered on Celite© and concentrated to afford a pale yellow solid. Thesolid was suspended in Et₂O and filtered. The residue was washed withcold Et₂O to give4-(pentafluoro-λ⁶-sulfanyl)-2-((phenylsulfonyl)methyl)aniline (22, 0.5g) as a white-pale yellow solid. More material was collected fromconcentration of the mother liquor as a pale yellow solid (0.7 g). Thesolids were combined to give4-(pentafluoro-λ⁶-sulfanyl)-2-((phenylsulfonyl)methyl)aniline (22, 1.2g, 3.5 mmol, quant) that was used in the next step without furtherpurification: ¹H NMR (400 MHz, MeOD) δ 7.79-7.71 (m, 3H), 7.68 (dd,J=9.1, 2.6 Hz, 1H), 7.59 (t, J=7.8 Hz, 2H), 7.39 (d, J=9.1 Hz, 1H), 7.06(d, J=2.5 Hz, 1H), 4.58 (s, 2H).

A suspension of4-(pentafluoro-λ⁶-sulfanyl)-2-[(phenylsulfonyl)methyl]aniline (22, 0.20g, 0.54 mmol), aldehyde 19 (0.49 g, 1.1 mmol), and MgSO₄ (0.32 g, 2.7mmol) in acetic acid (2 mL) was heated at 75° C. for 14 h, concentrated,basified with NaHCO₃ and extracted with EtOAc (3×). The combined organiclayers were washed with brine, dried (Na₂SO₄) and concentrated. Theresidue was dissolved in dry DMSO (4 mL) and added to a suspension ofpowdered KOH (0.15 g, 2.7 mmol) in dry DMSO (2 mL). The reaction mixturewas stirred at rt for 90 min, then acidified to pH 8 with sat. NH₄Cl,and extracted with EtOAc (3×). The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The crude residue waspurified by chromatography on SiO₂ (7:3, EtOAc/MeOH) to providetert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(pentafluoro-λ⁶-sulfanyl)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.030 g, 0.045 mmol, 8%) as a pale yellow foam: ¹H NMR (400 MHz, CDCl₃)δ 9.33 (s, 1H), 8.07 (d, J=1.8 Hz, 1H), 7.59 (dd, J=9.0, 2.1 Hz, 1H),7.41 (d, J=8.9 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.23 (s, 1H), 7.17 (d,J=7.6 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.88 (d, J=0.7 Hz, 1H), 3.82-3.79(m, 2H), 3.26 (t, J=1.1 Hz, 2H), 2.79-2.51 (m, 13H), 1.79 (s, 4H), 1.51(s, 9H), 1.08 (d, J=6.5 Hz, 6H).

A solution of trifluoroacetic acid (1 mL) in CH₂Cl₂ (1 mL) was added toa solution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(pentafluoro-λ⁶-sulfanyl)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.025 g, 0.037 mmol) in CH₂Cl₂ (1 mL). The reaction mixture was stirredunder N₂ at room temperature for 1 h, concentrated, diluted with NaHCO₃,extracted with EtOAc (3×), washed with brine, dried (Na₂SO₄) andconcentrated. The crude residue was purified by chromatography on SiO₂(100:8:1 to 100:15:1, CH₂Cl₂/MeOH/NEt₃). Purified fractions wereconcentrated and subsequently filtered through basic Al₂O₃ (100:0 then100:10, CH₂Cl₂/MeOH) to provideN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-(pentafluoro-λ⁶-sulfanyl)-1H-indol-2-yl)phenyl)piperidin-4-amine(13, 0.013 g, 0.023 mmol, 61%) as a white foam: IR (ATR) 3147, 2923,2852, 2815, 1603, 1458, 1383, 1148, 839, 809 cm⁻¹; ¹H NMR (400 MHz,MeOD) δ 8.05 (d, J=2.0 Hz, 1H), 7.55 (dd, J=9.0, 2.1 Hz, 1H), 7.48 (d,J=9.0 Hz, 1H), 7.43 (s, 1H), 7.34-7.29 (m, 2H), 6.99-6.96 (m, 2H), 3.82(d, J=12.6 Hz, 2H), 2.85-2.76 (m, 4H), 2.67-2.51 (m, 13H), 2.03 (d,J=11.7 Hz, 2H), 1.54 (dq, J=11.8, 3.2 Hz, 2H), 1.09 (d, J=6.5 Hz, 6H);¹³C NMR (100 MHz, MeOD) δ 152.0, 146.8, 146.7, 146.5, 141.5, 137.8,132.5, 129.3, 127.9, 118.5, 118.4, 118.3, 118.2, 116.6, 116.3, 113.3,110.1, 99.6, 57.0, 54.8, 54.5, 52.7, 42.4, 31.4, 17.3; HRMS (ESI) m/zcalcd for C₂₈H₃₉N₅F₅S [M+H]⁺ 572.2841, found 572.2836.

Synthesis ofN-(2-(4-Isopropylpiperazin-1-yl)ethyl)-1-(3-(5-nitro-1H-indol-2-yl)phenyl)piperidin-4-amine(23)

To a solution of phenylhydrazine (27, 1.80 g, 16.6 mmol) and3′-bromoacetophenone (15, 3.31 g, 16.6 mmol) in EtOH (100 mL) wastreated with AcOH (0.050 mL, 0.86 mmol). The mixture was heated atreflux for 2 h under nitrogen, and then concentrated. The residue wasrecrystallized from hexanes/EtOAc (4:1) and filtered to afford(E)-1-(1-(3-bromophenyl)ethylidene)-2-phenylhydrazine as a pale yellowsolid (4.30 g, 14.9 mmol, 90%). This compound was quite unstable and wasused immediately for the next conversion.

A suspension of P₂O₅ (12.8 g, 45.1 mmol) and concentrated H₃PO₄ (8 mL)was heated at 100° C. under nitrogen until it formed a clear solution.the temperature was increased to 120° C. and(E)-1-(1-(3-bromophenyl)ethylidene)-2-phenylhydrazine (2.00 g, 6.90mmol) was added in one portion. The reaction mixture was stirred for 1 hat 120° C., cooled to room temperature, and quenched with crushed iceand water to obtain a white suspension. The solid was filtered, dried onthe filter for 15 min, dissolved in Et₂O, dried (Na₂SO₄) andconcentrated to afford 2-(3-bromophenyl)-1H-indole (28, 1.70 g, 6.25mmol, 90%) as a pale yellow solid: Mp 153-154° C.; IR (ATR) 3430, 1562,1439, 1420, 1346, 1230, 1073, 1051, 776, 712, 664 cm⁻¹; ¹H NMR (500 MHz,CDCl₃) δ 8.26 (bs, 1H), 7.80 (t, J=2.0 Hz, 1H), 7.65 (dd, J=8.0, 0.5 Hz,1H), 7.57 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 7.45 (ddd, J=8.0, 1.9, 1.0 Hz,1H), 7.40 (dd, J=8.0, 0.5 Hz, 1H), 7.30 (t, J=8.0 Hz, 1H), 7.23 (ddd,J=8.1, 7.1, 1.1 Hz, 1H), 7.15 (ddd, J=7.9, 7.1, 0.9 Hz, 1H), 6.84 (dd,J=2.0, 1.0 Hz, 1H); ¹³C NMR (125 MHz, CDCl₃) δ 137.0, 136.2, 134.4,130.52, 130.49, 129.1, 128.1, 123.7, 123.2, 122.9, 120.9, 120.5, 111.0,101.0; FIRMS (ESI) m/z calcd for C₁₄H₁₁NBr [M+H]⁺ 272.0069, found272.0069.

A suspension of 2-(3-bromophenyl)-1H-indole (28, 5.49 g, 20.2 mmol) inconcentrated sulfuric acid (120 mL) at 5° C. was treated dropwise over30 min with a cold (5° C.) solution of sodium nitrate (1.82 g, 21.4mmol) in concentrated sulfuric acid (60 mL). The mixture was stirred for15 min, and then poured onto crushed ice. The yellow precipitate wasfiltered, dissolved in EtOAc (400 mL), washed with H₂O (3×100 mL), sat.NaHCO₃ (2×50 mL) and brine, dried (Na₂SO₄), filtered and concentrated.The give crude product (5.53 g) was suspended in MeOH (350 mL), stirredovernight and filtered to afford 2-(3-bromophenyl)-5-nitro-1H-indole(4.18 g, 13.2 mmol, 65%) as a bright yellow solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.37 (s, 1H), 8.55 (d, J=2.1 Hz, 1H), 8.14 (t, J=1.8 Hz,1H), 8.03 (dd, J=8.9, 2.3 Hz, 1H), 7.93 (ddd, J=7.8, 1.6, 1.1 Hz, 1H),7.61-7.56 (m, 2H), 7.47 (t, J=7.8 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H); HRMS(ESI) m/z calcd for C₁₄H₁₀O₂N₂Br [M+H]⁺ 316.9920, found 316.9918.

A suspension of 2-(3-bromophenyl)-5-nitro-1H-indole (0.15 g, 0.47 mmol),and LiHMDS (0.061 mg, 1.4 mmol) in dry deoxygenated THE (1.5 mL) wastreated with 17 (0.20 g, 0.57 mmol). The solution was purged with argonfor 20 min and treated with Pd₂(dba)₃ (0.009 g, 0.01 mmol) andCyJohnPhos (0.013 g, 0.038 mmol). The reaction mixture was heated at70-75° C. for 24 h in a sealed tube, quenched with sat. NaHCO₃ (2 mL)and extracted with EtOAc (3×3 mL). The combined organic layers werewashed with brine, dried (Na₂SO₄) and evaporated. The residue waspurified by chromatography on SiO₂, (10 to 20% MeOH/CH₂Cl₂) to givetert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-nitro-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.13 g, 0.31 mmol, 45%) as a yellowish foam: ¹H NMR (400 MHz, CDCl₃) δ9.84 (bs, 1H), 8.54 (d, J=2.0 Hz, 1H), 8.05 (dd, J=8.8, 2.4 Hz, 1H),7.42 (d, J=8.8 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.20-7.16 (m, 2H),6.94-6.83 (m, 2H), 4.06 (bs, 1H), 3.80-3.60 (m, 2H), 3.22 (bs, 2H),2.70-2.44 (m, 14H), 1.82-1.61 (m, 4H), 1.49 (s, 9H), 1.04 (d, J=6.4 Hz,6H); IRMS (ESI) m/z calcd for C₃₃H₄₇O₄N₆ [M+H]⁺ 591.3653, found591.3654.

A solution of TFA (0.14 mL, 1.9 mmol) in CH₂Cl₂ (0.5 mL) was treatedwith tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-nitro-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.020 g, 0.033 mmol) in CH₂Cl₂ (0.5 mL) and stirred for 1.5 h. thereaction mixture was concentrated, diluted with sat. NaHCO₃, andextracted with EtOAc (3×2 mL). The combined organic layers were washedwith brine, dried (Na₂SO₄), filtered, and evaporated. The residue waspurified by chromatography on SiO₂, (5 to 10% MeOH/CH₂Cl₂ with 0.1%Et₃N) followed by filtration through a plug of basic Al₂O₃ (0 to 10%MeOH/CH₂Cl₂) to giveN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-nitro-1H-indol-2-yl)phenyl)piperidin-4-amine(23, 0.006 g, 0.01 mmol, 36%) as a yellow foam: IR (ATR, neat) 2932,2823, 2106, 1660, 1601, 1508, 1472, 1465, 1457, 1327, 1294, 1178, 1070,753 cm⁻¹; ¹H NMR (500 MHz, acetone-d₆) δ 8.55 (d, J=2.5 Hz, 1H), 8.03(dd, J=9.0, 2.5 Hz, 1H), 7.56 (d, J=9.0 Hz, 1H), 7.48 (t, J=1.8 Hz, 1H),7.35-7.29 (m, 2H), 7.16 (d, J=1.0 Hz, 1H), 7.00 (ddd, J=7.8, 2.5, 1.4Hz, 1H), 3.79-3.75 (m, 2H), 2.90 (td, J=11.9, 2.1 Hz, 2H), 2.78-2.71 (m,6H), 2.67-2.57 (m, 3H), 2.48-2.41 (m, 10H), 1.99-1.95 (m, 2H), 1.50-1.43(m, 2H), 0.98 (d, J=6.5 Hz, 6H); ¹³C NMR (125 MHz, acetone-d₆) δ 152.3,142.4, 141.8, 140.1, 132.0, 129.7, 128.5, 116.84, 116.77, 116.1, 115.9,112.8, 111.2, 100.7, 58.2, 54.6, 54.0, 53.7, 48.5, 47.6, 43.5, 32.4,17.9; HRMS (ESI) m/z calcd for C₂₈H₃₉O₂N₆ [M+H]⁺ 491.3129, found491.3126.

Synthesis ofN-(2-(4-Isopropylpiperazin-1-yl)ethyl)-1-(3-(5-methyl-1H-indol-2-yl)phenyl)piperidin-4-amine(24)

A solution of 3-bromoacetophenone (2.00 g, 10.0 mmol), p-toluidine (1.29g, 12.1 mmol), and TsOH.H₂O (17 mg, 0.10 mmol) in toluene (50 mL) washeated overnight under Dean-Stark conditions. The reaction mixture wascooled to room temperature, concentrated, and purified by chromatographyon SiO₂ (0 to 5% EtOAc/hexanes) to provide(E)-1-(3-bromophenyl)-N-(p-tolyl)ethan-1-imine as a yellow oil (1.10 g,3.82 mmol, 38%) that was used without further purification.

A solution of (E)-1-(3-bromophenyl)-N-(p-tolyl)ethan-1-imine (0.246 g,0.854 mmol), Pd(OAc)₂ (18 mg, 0.080 mmol), and Cu(OAc)₂.H₂O (514 mg,2.57 mmol) in DMSO (3.0 mL) was heated at 90° C. for 5 h, cooled to roomtemperature, and diluted with EtOAc and H₂O. The layers were separatedand the aqueous layer was back-extracted with EtOAc. The combinedorganic layers were dried (NaSO₄) and concentrated. The residue wasabsorbed onto SiO₂ and purified by chromatography on SiO₂ (ISCO-Rf, 0 to20% EtOAc/hexanes) followed by trituration with Et₂O/hexanes (1/1) togive 2-(3-bromophenyl)-5-methyl-1H-indole (30, 0.156 g, 0.545 mmol, 64%)as an off white solid: Mp 189-190° C.; IR (ATR) 3428, 1575, 1450, 1420,1215, 1077, 798, 767, 667 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 8.20 (bs, 1H),7.79 (t, J=2.0 Hz, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.43-7.41 (m, 2H),7.31-7.27 (m, 2H), 7.04 (dd, J=1.0, 8.0 Hz, 1H), 6.75 (d, J=1.0 Hz, 1H),2.45 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 136.2, 135.3, 134.6, 130.5,130.3, 129.7, 129.3, 127.9, 124.5, 123.5, 123.1, 120.5, 110.6 (2C),21.4; HRMS (ESI) m/z calcd for C₁₅H₁₃NBr [M+H]⁺ 286.0226, found286.0224.

A solution of 2-(3-bromophenyl)-5-methyl-1H-indole (30, 0.143 g, 0.501mmol), LiHMDS (0.201 g, 1.20 mmol), Pd₂(dba)₃ (9 mg, 0.01 mmol), andCyJohnPhos (14 mg, 0.040 mmol) in anhydrous THE was treated withtert-butyl (2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate(17, 0.213 g, 0.601 mmol). The reaction mixture was heated at 75° C.overnight, cooled to room temperature, diluted with sat. NaHCO₃, andextracted with CH₂Cl₂ (3×). The combined organic layers were washed withbrine, dried (Na₂SO₄), evaporated, and purified by chromatography onSiO₂ (2 to 7% MeOH/CH₂Cl₂) to provide tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-methyl-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.124 g, 0.222 mmol, 44%) as a foam: IR (ATR) 3303, 2963, 2930, 2809,1685, 1663, 1599, 1465, 1450, 1174, 1146, 1010, 775 cm⁻¹; ¹H NMR (400MHz, CDCl₃) δ 8.96 (s, 1H), 7.39 (s, 1H), 7.27-7.24 (m, 2H), 7.20 (bs,1H), 7.13 (d, J=7.2 Hz, 1H), 6.99 (dd, J=8.0, 0.8 Hz, 1H), 6.82 (bd,J=7.2 Hz, 1H), 6.70 (s, 1H), 4.10 (bs, 1H), 3.70 (m, 2H), 3.23 (bs, 2H),2.68-2.44 (m, 16H), 1.72 (bs, 4H), 1.51 (s, 9H), 1.04 (d, J=6.4 Hz, 6H);¹³C NMR (100 MHz, CDCl₃) δ 155.5, 151.7, 138.6, 135.2, 133.5, 129.6,129.5, 129.1, 123.6, 120.1, 116.7, 116.0, 113.6, 110.6, 99.2, 79.9,54.5, 53.8, 49.6, 49.5, 48.6, 39.8, 30.0, 28.5, 21.5, 18.5; HRMS (ESI)m/z calcd for C₃₄H₅₀O₂N₅ [M+H]⁺ 560.3959, found 560.3932.

A solution of TFA (2.35 g, 20.4 mmol) in CH₂Cl₂ (1 mL) was added to asolution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-methyl-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(0.114 g, 0.204 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture wasstirred under an atmosphere of N₂ at room temperature for 1 h,concentrated, diluted with sat. NaHCO₃, and extracted with EtOAc (3×).The combined organic layers were washed with brine, dried (Na₂SO₄),concentrated, and purified by chromatography on SiO₂ (7 to 9%MeOH/CH₂Cl₂ with 0.1% TEA) followed by filtration on basicAl₂O₃(CH₂Cl₂/MeOH, 100:0 to 100:10) to provideN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-methyl-1H-indol-2-yl)phenyl)piperidin-4-amine(24, 68 mg, 0.15 mmol, 73%) as a yellow foam: IR (ATR) 2930, 2924, 2811,1599, 1457, 1448, 1379, 1344, 1189, 1176, 1144, 1117, 982, 775, 734cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.39 (d, J=0.7 Hz, 1H),7.30-7.26 (m, 2H), 7.21 (t, J=1.9 Hz, 1H), 7.10 (ddd, J=7.6, 1.4, 0.8Hz, 1H), 7.01-6.98 (ddd, J=8.0, 1.6, 0.4 Hz, 1H), 6.88 (dd, J=8.0, 2.1Hz, 1H), 6.70 (dd, J=2.1, 0.8 Hz, 1H), 3.73 (app d, J=12.6 Hz, 2H),2.86-2.76 (m, 4H), 2.68-2.48 (m, 12H), 2.44 (s, 3H), 2.00 (dd, J=12.6,2.2 Hz, 2H), 1.53 (dq, J=11.5, 3.0 Hz, 2H), 1.05 (d, J=6.5 Hz, 6H); ¹³CNMR (100 MHz, CDCl₃) δ 152.1, 138.8, 135.2, 133.5, 129.7, 129.6, 129.3,123.8, 120.3, 116.4, 115.9, 113.5, 110.6, 99.4, 58.1, 55.2, 54.6, 53.6,48.8, 48.7, 43.5, 32.7, 21.6, 18.8; IRMS (ESI) m/z calcd for C₂₉H₄₂N₅[M+H]⁺ 460.3435, found 460.3434.

Synthesis ofN-(2-(4-Isopropylpiperazin-1-yl)ethyl)-1-(3-(5-methoxy-1H-indol-2-yl)phenyl)piperidin-4-amine(25)

A solution of 3-bromoiodobenzene (32, 0.283 g, 1.00 mmol),5-methoxyindole (31, 0.147 g, 1.00 mmol), Pd(OAc)₂ (12 mg, 0.050 mmol),bis(diphenylphosphino)methane (20 mg, 0.05 mmol), and KOAc (0.297 g,3.00 mmol) in deoxygenated water (2 mL) was heated at 110° C. for 24 h,cooled to room temperature, diluted with ethyl acetate (10 mL) and 1 NHCl (5 mL), and extracted with ethyl acetate (2×10 mL). The combinedorganic layers were dried (MgSO₄), evaporated, and purified bychromatography on SiO₂ (10% EtOAc/hexanes) followed by recrystallizationfrom hexanes and CH₂Cl₂ to give 2-(3-bromophenyl)-5-methoxy-1H-indole(33, 0.133 g, 0.440 mmol, 44%) as a white solid: ¹H NMR (300 MHz, CDCl₃)δ 8.20 (bs, 1H), 7.77 (s, 1H), 7.55 (app d, J=7.7 Hz, 1H), 7.43 (app d,J=8.1 Hz, 1H), 7.30 (m, 2H), 7.08 (d, J=2.3 Hz, 1H), 6.88 (dd, J=8.8,2.4 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 3.87 (s, 3H); HRMS (ESI) m/z calcdfor C₁₅H₁₃ONBr [M+H]⁺ 302.0175, found 302.0174.

A solution of 33 (76 mg, 0.25 mmol), K₃PO₄ (82 mg, 0.38 mmol), Pd₂(dba)₃(5 mg, 0.005 mmol), CyJohnPhos (7 mg, 0.02 mmol) in anhydrous anddeoxygenated dioxane (1 mL) in a 2-5 mL conical sealed vessel wasdegassed by bubbling argon for 5 min. The reaction mixture was treatedwith tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate (17, 0.106g, 0.300 mmol) in dry dioxane (1.5 mL) and degassed for 15 min. Thevessel was sealed and heated at 110° C. for 11 h in a Biotage Initiatormicrowave reactor, cooled to room temperature, diluted with sat. NaHCO₃,and extracted with CH₂Cl₂ (3×). The combined organic layers were washedwith brine, dried (Na₂SO₄), evaporated, and purified by chromatographyon SiO₂ (2% MeOH/CH₂Cl₂ and 0.1% TEA) followed by chromatography onbasic Al₂O₃(CH₂Cl₂) to give tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-methoxy-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(46 mg, 0.080 mmol, 32%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.76(s, 1H), 7.28-7.25 (m, 2H), 7.18 (br s, 1H), 7.12 (d, J=7.6 Hz, 1H),7.07 (d, J=2.2 Hz, 1H), 6.85-6.81 (m, 2H), 6.71 (d, J=1.2 Hz, 1H), 4.11(br s, 1H), 3.85 (s, 3H), 3.74-3.72 (m, 2H), 3.29-3.19 (m, 2H),2.71-2.45 (m, 13H), 1.76-1.72 (m, 3H), 1.48 (s, 9H), 1.05 (d, J=6.5 Hz,6H); ¹³C NMR (100 MHz, CDCl₃) δ 155.5, 154.4, 151.8, 139.3, 133.5,132.1, 129.7, 116.7, 116.1, 113.6, 112.4, 111.8, 102.2, 99.6, 80.0,55.9, 49.6, 48.6, 30.11, 30.09, 28.6, 18.6.

A solution of TFA (0.599 mL, 7.99 mmol) and triethylsilane (0.129 mL,0.799 mmol) in CH₂Cl₂ (1 mL) was added to a solution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-methoxy-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(46 mg, 0.080 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture was stirredunder an atmosphere of N₂ at room temperature for 2 h, evaporated,diluted with sat. NaHCO₃, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (Na₂SO₄), evaporated, andpurified by chromatography on SiO₂ (7 to 9% MeOH/CH₂Cl₂ with 0.1% TEA)followed by chromatography on basic Al₂O₃ (0 to 9% MeOH/CH₂Cl₂) to giveN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-methoxy-1H-indol-2-yl)phenyl)piperidin-4-amine(25, 20 mg, 0.041 mmol, 51%) as a yellow oil: IR (ATR) 3221, 2924, 2818,1577, 1452, 1881, 1381, 1204, 1176, 1146, 1114, 839, 775 cm⁻¹; ¹H NMR(400 MHz, CDCl₃) δ 8.74 (bs, 1H), 7.29 (m, 2H), 7.21 (app t, J=1.9 Hz,1H), 7.11 (app d, J=7.8 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 6.87 (dd,J=8.1, 2.1 Hz, 1H), 6.83 (dd, J=8.8, 2.4 Hz, 1H), 6.71 (app d, J=1.0 Hz,1H), 4.01 (bs, 2H), 3.85 (s, 3H), 3.72 (app d, J=12.6 Hz, 2H), 2.84-2.51(m, 16H), 2.00 (m, 3H), 1.56 (qd, J=11.6, 3.0 Hz, 2H), 1.06 (d, J=6.5Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 154.5, 152.0, 139.5, 133.5, 132.2,129.8, 116.6, 116.0, 113.5, 112.4, 111.8, 102.3, 99.7, 57.4, 56.0, 55.0,54.7, 53.1, 48.67, 48.54, 43.0, 32.1, 18.5; HRMS (ESI) m/z calcd forC₂₉H₄₂ON₅ [M+H]⁺ 476.3384, found 476.3383.

Synthesis ofN-(2-(4-Isopropylpiperazin-1-yl)ethyl)-1-(3-(5-(trifluoromethoxy)-1H-indol-2-yl)phenyl)piperidin-4-amine(26)

A solution of 3-bromoacetophenone (15, 1.00 g, 5.02 mmol),4-(trifluoromethoxy)aniline (1.07 g, 6.04 mmol), and TsOH.H₂O (8.7 mg,0.046 mmol) in toluene (50 mL) was heated under Dean-Stark conditionsovernight. The reaction mixture was cooled to room temperature,concentrated, and purified by chromatography on SiO₂ (0 to 5%EtOAc/hexanes) to give(E)-1-(3-bromophenyl)-N-(4-(trifluoromethoxy)phenyl)ethan-1-imine as ayellow oil (0.91 g, 2.5 mmol, 51%): ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s,1H), 7.88-7.86 (m, 1H), 7.62-7.59 (m, 1H), 7.32 (td, J=7.6, 0.4 Hz, 1H),7.21 (app d, J=8.8 Hz, 2H), 6.81-6.77 (m, 2H), 2.22 (s, 3H).

A solution of(E)-1-(3-bromophenyl)-N-(4-(trifluoromethoxy)phenyl)ethan-1-imine (75mg, 0.21 mmol), Pd(OAc)₂ (5 mg, 0.02 mmol), and TBAB (0.13 g, 0.40 mmol)in DMSO (1 mL) in a Schlenk tube was purged, filled with oxygen andheated at 60° C. for 24 h. The reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (5 mL), and filtered throughSiO₂. The filtrate was washed with 1 M NaHSO₃, concentrated and purifiedby chromatography on SiO₂ (30% CH₂Cl₂/hexanes) to give2-(3-bromophenyl)-5-(trifluoromethoxy)-1H-indole (35, 62 mg, 0.17 mmol,83%): ¹H NMR (400 MHz, CDCl₃) δ 8.36 (bs, 1H), 7.78 (s, 1H), 7.55 (d,J=7.6 Hz, 1H), 7.48-7.46 (m, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.31 (app t,J=8.0 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H), 6.81 (s, 1H); ¹³C NMR (100 MHz,CDCl₃) δ 143.7, 138.2, 135.3, 134.0, 131.1, 130.7, 129.3, 128.3, 123.9,123.4, 120.9 (q, J_(CF)=255.3 Hz), 116.9, 113.3, 111.7, 101.3; HRMS(ESI) m/z calcd for C₁₅H₁₀ONBrF₃ [M+H]⁺ 355.9892, found 355.9891.

A solution of 35 (89.1 mg, 0.250 mmol), K₃PO₄ (82 mg, 0.39 mmol),Pd₂(dba)₃ (4.70 mg, 0.005 mmol), and CyJohnPhos (7.20 mg, 0.020 mmol) inanhydrous and deoxygenated dioxane (1 mL) in a 2-5 mL conical sealedvial was degassed by bubbling argon for 5 min. The reaction mixture wastreated with a solution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(piperidin-4-yl)carbamate (17, 0.106g, 0.299 mmol) in dry dioxane (1.5 mL) and degassed for 15 min. The vialwas sealed and heated at 110° C. for 11 h in a Biotage Initiatormicrowave reactor, cooled to room temperature, diluted with sat. NaHCO₃,and extracted with CH₂Cl₂ (3×). The organic layers were combined, washedwith brine, dried (Na₂SO₄), evaporated, and purified by chromatographyon SiO₂ (2% MeOH/CH₂Cl₂ with 0.1% TEA) followed by chromatography onbasic Al₂O₃(CH₂Cl₂) to give tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(trifluoromethoxy)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(46 mg, 0.073 mmol, 29%) as a light yellow oil: IR (ATR) 3266, 2969,2961, 2952, 2933, 2928, 2818, 2810, 1681, 1664, 1601, 1478, 1465, 1450,1413, 1383, 1366, 1346, 1329, 1301, 1253, 1217, 1152, 1010, 1003, 995,973, 895, 867 cm⁻¹; ¹H NMR (400 MHz, acetone-d₆) δ 10.47 (s, 1H),6.97-6.93 (m, 3H), 6.80-6.76 (m, 2H), 6.52 (d, J=8.8 Hz, 1H), 6.45-6.43(m, 2H), 3.40 (d, J=12.0 Hz, 2H), 2.72 (bs, 2H), 2.48 (bs, 2H), 2.29(app t, J=11.6 Hz, 2H), 1.93-1.89 (m, 9H), 1.52 (app s, 1H), 1.42 (bs,2H), 1.24 (bs, 2H), 0.93 (s, 9H), 0.43 (d, J=6.4 Hz, 6H); ¹³C NMR (100MHz, acetone-d₆) δ 155.6, 152.8, 143.7, 141.9, 136.6, 133.6, 130.5,130.3, 129.1, 128.4, 121.8 (q, J_(CF)=253.2 Hz), 117.0, 116.7, 116.0,113.8, 113.1, 112.8, 100.1, 79.5, 54.9, 54.8, 50.0, 49.3, 28.7, 18.7;HRMS [ESI] m/z calcd for C₃₄H₄₇O₃N₅F₃ [M+H]⁺ 630.3626, found 630.3628.

A solution of TFA (0.50 mL) and triethylsilane (0.10 mL, 0.64 mmol) inCH₂Cl₂ (1 mL) was added to a solution of tert-butyl(2-(4-isopropylpiperazin-1-yl)ethyl)(1-(3-(5-(trifluoromethoxy)-1H-indol-2-yl)phenyl)piperidin-4-yl)carbamate(40 mg, 0.064 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture was stirredunder an atmosphere of N₂ at room temperature for 1 h, concentrated,diluted with sat. NaHCO₃, and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried (Na₂SO₄), concentrated, andpurified by chromatography on SiO₂ (7 to 9% MeOH/CH₂Cl₂ with 0.1% TEA)followed by chromatography on basic Al₂O₃ (0 to 9% MeOH/CH₂Cl₂) to giveN-(2-(4-isopropylpiperazin-1-yl)ethyl)-1-(3-(5-(trifluoromethoxy)-1H-indol-2-yl)phenyl)piperidin-4-amine(26, 15 mg, 0.028 mmol, 45%) as a light yellow foam: IR (ATR) 2975,2818, 1670, 1458, 1254, 1199, 1174, 1130, 829, 800, 783, 719 cm¹; ¹H NMR(400 MHz, CDCl₃) δ 9.02 (s, 1H), 7.45 (d, J=1.2 Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 7.30 (app t, J=7.6 Hz, 1H), 7.24 (app t, J=1.6 Hz, 1H),7.14-7.11 (m, 1H), 7.03 (ddd, J=8.8, 2.4, 0.8 Hz, 1H), 6.90 (ddd, J=8.4,2.4, 0.8 Hz, 1H), 6.77 (app d, J=1.2 Hz, 1H), 3.74 (app d, J=12.8 Hz,2H), 2.86-2.52 (m, 16H), 2.01 (dd, J=12.7, 2.3 Hz, 2H), 1.59 (qd,J=12.8, 4.0 Hz, 2H), 1.08 (d, J=6.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ152.0, 143.4, 140.7, 135.2, 133.0, 129.9, 129.5, 121.0 (q, J_(CF)=255.2Hz), 116.7, 116.4, 116.1, 113.7, 112.9, 111.6, 100.1, 57.1, 55.2, 55.0,52.9, 48.5, 43.0, 31.9, 18.4; HRMS [ESI] m/z calcd for C₂₉H₃₉ON₅F₃[M+H]⁺ 530.3101, found 530.3100.

Biological Assays

To optimize p97 inhibitors, the C-5 trifluoromethylatedtrifluoromethylated indole 12 was generated as a promising leadstructure. In the ADP-Glo assay, it was determined that this compoundexhibits a 5.96±1.66 μM IC₅₀ value (Table 1), after which the effect ofreplacing the CF₃— with an SF₅-group at the C-5 position as shown forcompound 13 was explored. The ADP-Glo assay can be conducted asdescribed in Chou, T.-F.; Bulfer, S. L.; Weihl, C. C.; Li, K.; Lis, L.G.; Walters, M. A.; Schoenen, F. J.; Lin, H. J.; Deshaies, R. J.; Arkin,M. R., “Specific inhibition of p97/VCP atpase and kinetic analysisdemonstrate interaction between D1 and D2 ATPase domains.” J. Mol. Biol.2014, 426, 2886-2899.

Surprisingly, replacement of the trifluoromethyl with apentafluorosulfanyl group reduced the p97 inhibition almost 4-fold to anIC₅₀ of 21.48±0.49 μM. It was hypothesized that this decrease couldeither be due to the larger size of the SF₅ group or its strongerelectron-withdrawing effect on the indole ring. Accordingly, thecorresponding nitro (23), methyl (24), methoxy (25), andtrifluoromethoxy (26) analogs were prepared to test these parameters.

Electron-density surfaces encoded with electrostatic potential maps forthe indole segments of these compounds illustrate both their stericfeatures as well as the range of their inductive effects on the aromaticπ-system (FIG. 3). Sterically, SF₅-analog 13 and CF₃O-analog 26 are theclosest match, but their electronic effects on the indole ring and theindole nitrogen are significantly different. As expected, nitro-analog23 is the best electronic match of the pentafluorosulfanyl derivative.Sterically, and, in particular, electronically, CH₃O-analog 25 is mostclosely related to CH₃-analog 24. Arguably, CF₃-analog 12 is somewhatunique in this series, but sterically its closest match would beNO₂-analog 23 and CH₃-analog 24, whereas electronically it is situatedbetween SF₅-analog 13 and CF₃O-analog 26. Accordingly, it was expectedthat the methylated indole 24 would have similar activity to 12 ifsteric effects were dominant, whereas electronic effects would likelyfavor ethers 25 and 26, since the bulkier and more electron-deficientpentafluorosulfanyl had registered a significant drop in activity.

Evaluation of 23-26 in the p97 ADP-Glo assay revealed a remarkable threeorders of magnitude range of activities between the six indoles (Table2). Nitro-analog 23 was found to be a 40 nM inhibitor of the AAAATPase(Entry 3, IC₅₀ 0.04±0.04 μM). CF₃O-analog 26 was considerably lessactive (Entry 6, IC₅₀ 3.72±0.77 μM), but showed higher activity thanCF₃-analog 12. Methylated 24 and methoxylated 25 had intermediate butstill sub-micromolar IC₅₀'s (Entries 4 and 5, IC₅₀ 0.20±0.12 μM and0.66±0.20 μM, respectively).

TABLE 2 Biochemical Activities of p97 Inhibitors^(a) Compound/p97-ADPGlo p97-ADPGlo Entry R-Group IC₅₀ [μM] Std. Dev. [μM] 1 12/CF₃4.7  ±2.0  2 13/SF₅ 21.5 ±0.4  3 23/NO₂ 0.05 ±0.04 4 24/CH₃ 0.24 ±0.11 525/OCH₃ 0.71 ±0.22 6 26/OCF₃ 3.8  ±0.8  ^(a)Assay conditions: ADP Glowith p97 ATPase WT in the presence of 100 μM ATP. Assays were run inquadruplicate (12, 13, 25, 26), seven times (24), or nine times (23).

TABLE 3 Biochemical Activities of p97 Inhibitors ADP- ADP- Glo Glo IC₅₀IC₅₀ Structure (μM) Structure (μM)

0.1

0.51

0.3

0.54

0.21

0.63

0.17

0.64

0.14

0.66

0.38

0.67

0.38

0.68

0.19

0.7

0.45

0.71

0.3

0.76

0.8

0.8

0.81

0.85

1

0.89

0.74

0.96

0.72

1.1

0.57

1.1

0.89

1.3

0.88

1.3

0.91

1.3

1

1.3

1.7

1.3

1.4

1.4

2.7

1.7

13

1.7

0.015

1.8

0.015

1.9

0.025

2.2

0.026

2.4

0.026

2.4

0.027

3.3

0.036

3.7

0.041

3.8

0.047

3.8

0.049

3.9

0.082

4.139

0.086

4.3

0.087

4.5

0.092

4.6

0.1

4.9

0.1

5.1

0.11

5.2

0.11

5.3

0.11

5.6

0.11

5.8

0.12

6

0.12

6

0.13

6.1

0.13

6.2

0.13

7.1

0.13

7.34

0.14

7.5

0.14

7.58

0.14

7.6

0.15

8

0.15

8.6

0.15

9.3

0.15

9.7

0.16

11

0.175

11

0.18

12

0.2

12

0.2

13.587

0.26

14

0.29

14

0.29

15

0.31

15.773

0.32

16

0.32

16

0.32

17

0.33

19

0.34

20

0.35

20

0.37

21

0.37

22

0.41

23

0.43

23

0.43

24

0.44

25

0.46

0.5

Additional Embodiments

E1. A compound having the structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:R¹ is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,—N═N⁺═N⁻, an optionally substituted C₁-C₃ alkyl, an optionallysubstituted C₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted 6-10membered aryl, an optionally substituted 5-10 membered heteroaryl,—S(O)₂R⁵, —OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or —S(Z)₅;each of R⁵ or R⁶ is independently H, D, an optionally substituted C₁-C₅alkyl, an optionally substituted C₁-C₃ alkoxy, or R⁵ and R⁶, togetherwith the intervening atoms to which they are attached, can form a 5-6membered ring;Z is a halo;ring B is 6-10 membered aryl, a 5-10 membered heteroaryl, or a 5-10membered heterocyclyl;R² is H, D, halo, cyano, or an optionally substituted C₁-C₃ alkyl;m is 0, 1, 2, 3, or 4;R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and R³,together with the intervening atoms to which they are attached, can forma 5-6 membered ring;L¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—; —NR⁵C(O)O—;—C(O)NR⁶—; —S(O)—; or —S(O)₂—;

X is CH or N;

Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;L² is a bond, an optionally substituted C₁-C₅ alkyl, or an optionallysubstituted 3-10 membered cycloalkyl;A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl, anoptionally substituted 4-10 membered heterocyclyl, an optionallysubstituted 5-10 membered heteroaryl, an optionally substituted 6-10membered aryl, or an optionally substituted 4-7 membered cycloalkyl;each R¹⁰ independently is H, an optionally substituted C₁-C₃ alkyl, anoptionally substituted 5-7 membered heteroaryl, or an optionallysubstituted 6-10 membered aryl;p is 0, 1, 2, 3, or 4; and

denotes a single or double bond;wherein the compound is not:

E2. The compound of E1, wherein X is N.

E3. The compound of one of E1-E2, wherein Y is NH.

E4. The compound of any of E1-E3, wherein A is a 5-10 memberedheterocyclyl.

E5. The compound of any of E1-E4, wherein at least one ring heteroatomof A is N.

E6. The compound of any of E1-E5, wherein A has the structure:

wherein each R³ is independently CH or N and M is an optionallysubstituted C₁-C₆ alkyl.

E7. The compound of E6, wherein A has the structure:

E8. The compound of any of E1-E7, wherein M is a C₁-C₃ alkyl.

E9. The compound of any of E1-E8, wherein L² is an optionallysubstituted C₁-C₃ alkyl.

E10. The compound of any of E1-E9, wherein L² is an optionallysubstituted C₂ alkyl.

E11. The compound of any of E1-E10, wherein R¹ is halo, cyano, N(O)₂,hydroxyl, or —C(O)NR⁵R⁶.

E12. The compound of any of E1-E11, wherein p is 0.

E13. A compound of formula (I), selected from the group consisting ofthe compounds of Table 1, or a pharmaceutically acceptable salt thereof.

E14. A pharmaceutical composition comprising a compound of any of E1-E12and at least one pharmaceutically acceptable excipient.

E15. A pharmaceutical composition comprising a compound of E13 and atleast one pharmaceutically acceptable excipient.

E16. A method of inhibiting p97 in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of formula II or a therapeutically effective amount of apharmaceutical composition comprising a compound of formula II and atleast one pharmaceutically acceptable excipient:

or a pharmaceutically acceptable salt thereof, wherein:R¹ is H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,—N═N⁺═N⁻, an optionally substituted C₁-C₃ alkyl, an optionallysubstituted C₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted 6-10membered aryl, an optionally substituted 5-10 membered heteroaryl,—S(O)₂R⁵, —OCZ₃, —OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or S(Z)₅;each of R⁵ or R⁶ is independently H, D, an optionally substituted C₁-C₅alkyl, an optionally substituted C₁-C₃ alkoxy, or R⁵ and R⁶, togetherwith the intervening atoms to which they are attached, can form a 5-6membered ring;Z is a halo;ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a 5-10membered heterocyclyl;R² is H, D, halo, cyano, or an optionally substituted C₁-C₃ alkyl;m is 0, 1, 2, 3, or 4;R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and R³,together with the intervening atoms to which they are attached, can forma 5-6 membered ringL¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—; —NR⁵C(O)O—;—C(O)NR⁶—; —S(O)—; or —S(O)₂—;

X is CH or N;

Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;L² is a bond, an optionally substituted C₁-C₅ alkyl, or an optionallysubstituted 3-10 membered cycloalkyl;A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl, anoptionally substituted 4-10 membered heterocyclyl, an optionallysubstituted 5-10 membered heteroaryl, an optionally substituted 6-10membered aryl, or an optionally substituted 4-7 membered cycloalkyl;each R¹⁰ independently is H, an optionally substituted C₁-C₃ alkyl, anoptionally substituted 5-7 membered heteroaryl, or an optionallysubstituted 6-10 membered aryl;p is 0, 1, 2, 3, or 4; and

denotes a single or double bond.

E17. A method of treating cancer or a neurodegenerative diseasesusceptible to treatment by p97 inhibition in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of a compound of formula II or a therapeutically effective amountof a pharmaceutical composition comprising a compound of formula II andat least one pharmaceutically acceptable excipient:

or a pharmaceutically acceptable salt thereof, wherein:R¹ is a H, D, halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵,—N═N═N, an optionally substituted C₁-C₃ alkyl, an optionally substitutedC₁-C₃ alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted 6-10 membered aryl,an optionally substituted 5-10 membered heteroaryl, —S(O)₂R⁵, —OCZ₃,—OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or S(Z)₅;each of R⁵ or R⁶ is independently H, D, an optionally substituted C₁-C₅alkyl, an optionally substituted C₁-C₃ alkoxy, or R⁵ and R⁶, togetherwith the intervening atoms to which they are attached, can form a 5-6membered ring;Z is a halo;ring B is a 6-10 membered aryl, a 5-10 membered heteroaryl, or a 5-10membered heterocyclyl;R² is H, D, halo, cyano, or an optionally substituted C₁-C₃ alkyl;m is 0, 1, 2, 3, or 4;R³ is H, D, or an optionally substituted C₁-C₃ alkyl; or R² and R³,together with the intervening atoms to which they are attached, can forma 5-6 membered ringL¹ is a bond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—; —NR⁵C(O)O—;—C(O)NR⁶—; —S(O)—; or —S(O)₂—;

X is CH or N;

Y is a bond, CH, CH₂, CH₃, N, NH, NH₂, O, or S;L² is a bond, an optionally substituted C₁-C₅ alkyl, or an optionallysubstituted 3-10 membered cycloalkyl;A is —NR¹⁰R¹⁰, —C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl, anoptionally substituted 4-10 membered heterocyclyl, an optionallysubstituted 5-10 membered heteroaryl, an optionally substituted 6-10membered aryl, or an optionally substituted 4-7 membered cycloalkyl;each R¹⁰ independently is H, an optionally substituted C₁-C₃ alkyl, anoptionally substituted 5-7 membered heteroaryl, or an optionallysubstituted 6-10 membered aryl;p is 0, 1, 2, 3, or 4; and

denotes a single or double bond.

E18. A method of inhibiting p97 in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of acompound of any one of E1-16 or a therapeutically effective amount of apharmaceutical composition of E14 or E15.

E19. A method of treating cancer or a neurodegenerative diseasesusceptible to treatment by p97 inhibition in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of a compound of any one of E1-E13 or a therapeutically effectiveamount of E14 or E15.

E20. The method of any one of E17-E19, wherein the cancer susceptible totreatment by p97 inhibition is selected from the group consisting of asolid tumor, non-small cell lung carcinoma, multiple myeloma, and mantlecell lymphoma.

E21. The method of any one of E17-E19, wherein the neurodegenerativedisease susceptible to treatment is selected from the group consistingof inclusion body myopathy (IBM), Paget's disease of the bone (PDB),frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS).

1-15. (canceled)
 16. A method of treating a neurodegenerative diseasesusceptible to treatment by p97 inhibition in a subject in need thereof,comprising: administering to the subject a therapeutically effectiveamount of a compound of formula II, or a therapeutically effectiveamount of a pharmaceutical composition comprising a compound of formulaII and at least one pharmaceutically acceptable excipient:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, D,halo, cyano, hydroxyl, nitro, —C(O)NR⁵R⁶, —C(O)OR⁵, —N═N⁺═N⁻, anoptionally substituted C₁-C₃ alkyl, an optionally substituted C₁-C₃alkoxy, —S(O)₂NR⁵R⁶, an optionally substituted 6-10 membered aryl, anoptionally substituted 5-10 membered heteroaryl, —S(O)₂R⁵, —OCZ₃,—OCHZ₂, —OCH₂Z, —SZ₃, —SCZ₃, or S(Z)₅; each of R⁵ or R⁶ is independentlyH, D, an optionally substituted C₁-C₅ alkyl, an optionally substitutedC₁-C₃ alkoxy, or R⁵ and R⁶, together with the intervening atoms to whichthey are attached, can form a 5-6 membered ring; Z is a halo; ring B isa 6-10 membered aryl, a 5-10 membered heteroaryl, or a 5-10 memberedheterocyclyl; R² is H, D, halo, cyano, or an optionally substitutedC₁-C₃ alkyl; m is 0, 1, 2, 3, or 4; R³ is H, D, or an optionallysubstituted C₁-C₃ alkyl; or R² and R³, together with the interveningatoms to which they are attached, can form a 5-6 membered ring L¹ is abond; —C(O)—; —C(O)O—; —OC(O)—; —NR⁵C(O)NR⁶—; —NR⁵C(O)O—; —C(O)NR⁶—;—S(O)-; or —S(O)₂—; X is CH or N; Y is a bond, CH, CH₂, CH₃, N, NH, NH₂,O, or S; L² is a bond, an optionally substituted C₁-C₅ alkyl, or anoptionally substituted 3-10 membered cycloalkyl; A is —NR¹⁰R¹⁰,—C(O)OR¹⁰, an optionally substituted C₁-C₅ alkyl, an optionallysubstituted 4-10 membered heterocyclyl, an optionally substituted 5-10membered heteroaryl, an optionally substituted 6-10 membered aryl, or anoptionally substituted 4-7 membered cycloalkyl; each R¹⁰ independentlyis H, an optionally substituted C₁-C₃ alkyl, an optionally substituted5-7 membered heteroaryl, or an optionally substituted 6-10 memberedaryl; p is 0, 1, 2, 3, or 4; and

denotes a single or double bond. 17.-20. (canceled)
 21. The method ofclaim 16, wherein the neurodegenerative disease susceptible to treatmentis selected from the group consisting of inclusion body myopathy (IBM),Paget's disease of the bone (PDB), frontotemporal dementia (FTD) andamyotrophic lateral sclerosis (ALS).
 22. The method of claim 21, whereinthe neurodegenerative disease is IBM.
 23. The method of claim 21,wherein the neurodegenerative disease is PDB.
 24. The method of claim21, wherein the neurodegenerative disease is FTD.
 25. The method ofclaim 21, wherein the neurodegenerative disease is ALS.
 26. The methodof claim 16, wherein the neurodegenerative disease is a multisystemdegenerative disorder characterized by one or more of four mainphenotypes, which are inclusion body myopathy (IBM), Paget's disease ofthe bone (PDB), frontotemporal dementia (FTD) and amyotrophic lateralsclerosis (ALS).
 27. The method of claim 16, wherein theneurodegenerative disease is characterized by one or more symptomsselected from the group consisting of Parkinsonism, ataxia, cataracts,dilated cardiomyopathy, hepatic fibrosis, and hearing loss.
 28. Themethod of claim 16, wherein the neurodegenerative disease is amultisystem proteinopathy.
 29. The method of claim 28, wherein themultisystem proteinopathy is characterized by penetrance of muscle, boneand CNS degenerative phenotypes along with the accumulation of ubiquitinand TDP-43-positive inclusions.
 30. The method of claim 16, wherein theneurodegenerative disease is caused by proteostatic malfunction.
 31. Themethod of claim 16, wherein the compound of formula II is administeredin an amount sufficient to cure, or at least partially arrest, thesymptoms of the disease, including its complications and intermediatepathological phenotypes in development of the disease.
 32. The method ofclaim 16, wherein X is N.
 33. The method of claim 16, wherein Y is NH.34. The method of claim 16, wherein A is a 5-10 membered heterocyclyl.35. The method of claim 16, wherein at least one ring heteroatom of A isN.
 36. The method of claim 16, wherein A has the structure:

wherein each R³ is independently CH or N and M is an optionallysubstituted C₁-C₆ alkyl.
 37. The method of claim 36, wherein A has thestructure:


38. The method of claim 37, wherein M is a C₁-C₃ alkyl.
 39. The methodof claim 16, wherein R¹ is H, D, halo, cyano, hydroxyl, nitro, or—N═N⁺═N⁻.
 40. The method of claim 16, wherein R¹ is halo, cyano, N(O)₂,hydroxyl, or —C(O)NR⁵R⁶.
 41. The method of claim 7, wherein both R³ areN.
 42. The method of claim 16, wherein L² is an optionally substitutedC₁-C₃ alkyl.
 43. The method of claim 16, wherein L² is a C₂ alkyl. 44.The method of claim 16, wherein p=0.
 45. The method of claim 16, whereinthe compound of formula (II) is selected from the group consisting of: